Since the beginning of civilization, humanity has struggled with many epidemics of infectious diseases. After they had been defeated, mankind faced another problem of epidemic or rather pandemic proportions, i.e., non-communicable diseases. Currently, non-communicable diseases are the main cause of morbidity and mortality around the world. Diabetes mellitus (DM) was the first non-communicable disease that was recognized by the United Nations as a 21st-century pandemic problem [1
]. DM is a metabolic disease, characterized by an inappropriately elevated blood glucose level. DM is divided into several types that are based on the pathogenesis of the disease. The two most common forms of the condition are type 1 and type 2 DM. Table 1
provides a concise comparison of these two types of DM.
Type 1 diabetes mellitus (T1DM), which was previously known as insulin-dependent, or childhood diabetes, is characterized by a deficiency in insulin production and, thus, requires constant administration of exogenous insulin. Recent scientific reports suggest that people with T1DM also develop insulin resistance (IR), a phenomenon that is generally considered to be a distinctive feature of T2DM. Therefore, this review will focus on the pathogenesis of IR in T1DM, as well as its quaternary prevention and treatment [2
Interestingly, the majority of people with diagnosed DM live in the Western Pacific (131 million) and South-East Asian Regions (96 million) [3
]. However, the population of people with DM in the European (64 million) and American (62 million) Regions is also quite large [3
]. This spatial distribution may be due to the increase in the number of overweight and obese people in those regions [4
]. According to the WHO report, nowadays, one in three adults is overweight, and more than one in 10 is obese [3
]. In 2014, it was estimated that 422 million adults (8.5% of the world adult population) live with DM, when compared to 108 million in 1980 (4.7% of the world adult population) [3
]. DM is the seventh leading cause of death and a major cause of costly and debilitating complications, such as heart attack, stroke, kidney failure, blindness, and lower-limb amputation.
3. What Does It Mean to Be Insulin Resistant?
Insulin resistance is clinically defined as a reduced response of target tissues to stimulation by insulin. The phenomenon of IR is accompanied by a pathological insulin secretion after a meal, which is called hyperinsulinemia. Interestingly, long-lasting hyperinsulinemia leads to aggravated IR. In line with that notion, a chronically elevated insulin level (e.g., due to improper insulin injections) produces an adaptive reduction in the number of plasma membrane receptors for the hormone (due to their adaptive internalization and degradation) [6
]. Consequently, greater insulin dosage is required to elicit the same physiological effect, hence IR begins. Moreover, secondary alterations in target tissues are also possible. Marban et al. demonstrated that transgenic mice over-expressing insulin showed diminished insulin responsiveness despite fasting normoglycaemia and proper body weight [7
]. This could be explained by an impaired binding of insulin to its receptors and/or stem from hypertriglyceridemia, which may impair insulin signal transduction [8
]. Hyperinsulinemia may also promote weight gain, since insulin overdose results in severe hypoglycaemia and polyphagia (excessive eating) [9
]. This leads to the formation of a specific vicious circle, i.e., hyperinsulinemia propels IR and weight gain, which, in turn, require higher insulin dosage for compensation. Moreover, also defects in the insulin receptor structure, a reduction in the density of the receptors at the cell surface, or improper action of the immune system, may lead to an abnormal response of target tissues to insulin.
The possibility of the existence of reduced tissue insulin sensitivity in children, adolescents, and adults that are diagnosed with T1DM is no longer put into question. The development of IR in T1DM may be triggered by many risk factors (presented in Figure 1
). A key role in the initiation of IR in T1DM is attributed to the complex interactions between the genetic predisposition of an individual and their lifestyle. The human leukocyte antigen (HLA) accounts for most of the aforementioned genetic susceptibility to IR in T1DM. A study conducted by Todd et al. suggests that only the amino acid in position 57 of the DQB3-chain is strongly correlated with IR in T1DM [10
]. IR is often associated with being overweight and/or obese. Therefore, priority has been given to non-pharmacological approaches that can inhibit the development of obesity in T1DM. Excessive adipose tissue mass leads to the development of IR by the overproduction of hormones antagonistic to insulin (growth hormone, glucagon, cortisol, and catecholamines), and through a direct secretion of increased amount of free fatty acids (FFA) into the blood. In the case of exorbitant FFA level, the body begins to use them as an energy source instead of glucose. Consequently, glucose is not underoxidized in the tissues and, thus, its level in the blood increases. Subsequently, insulin secretion is increased in order to maintain a normal blood glucose level. Moreover, chronically elevated FFA level in the blood may lead to their accumulation in peripheral tissues, where they may interfere with insulin signal transduction [11
]. This is especially true for skeletal muscle, i.e., a tissue accountable for even 80% of insulin stimulated glucose uptake that takes place after a meal [12
]. Under physiological conditions, insulin binds to its receptor and initiates the embedding of glucose transporters type 4 (GLUT-4) into the myocyte plasma membrane. The process is guided by a cascade of secondary signal transducers, the most important of which are: IRS-1, PI3K, PKB/Akt, and AS160 [13
]. An excessive intracellular lipid build-up, especially into bioactive diacylglycerol (DAG) and ceramide (CER) species, disrupts this pathway. DAG, for instance, is known to activate protein kinase C (e.g., PKC θ) that inactivates IRS-1 (insulin receptor substrate 1). Ceramide, on the other hand, disables both IRS-1 (via activation of JNK) and protein kinase B (PKB/Akt) (via its proxy PP2A) [13
]. Interestingly, Conway et al., in the Pittsburgh Epidemiology of Diabetes Complications Study, showed that, amongst adults with T1DM, the prevalence of overweight and obese individuals increased from 29% to 42%, and from 3% to 23%, respectively [15
]. The participants were first seen in 1986–1988 (mean age and DM duration, were 29 and 20 years, respectively), and then after 18 years. Conway et al. suggested that the predictors of weight gain were: higher baseline hemoglobin A1c (HbA1c) concentration (directly related), symptomatic autonomic neuropathy (inversely related), overt nephropathy (inversely related), and intensive insulin therapy during follow-up (directly related) [15
]. Fellinger et al. showed that patients with T1DM have higher BMI values when compared to the general population of Austria. However, the higher BMI values were observed for a group of the T1DM patients aged 30–49. This may be due to the fact that, in this age group, insulin therapy was conducted from the beginning of the diagnosis of T1DM. The higher BMI values were not related to 10.2% poorer glycemic level, which was examined by HbA1c [16
]. Table 2
outlines a summary of the mechanisms that are involved in the etiopathogenesis of IR related to obesity. Unsurprisingly, it seems that, with worse metabolic stability of diabetes, IR severity also increases. The toxic effects of hyperglycemia and some lipid fractions also favor an increase in the resistance of insulin-dependent tissues to the action of insulin, thus enhancing IR and its metabolic consequences.
Oxidative stress interferes with insulin signaling, since reactive oxygen species (ROS) may induce insulin receptor substrate (IRS) serine/threonine phosphorylation, impair cellular redistribution of insulin signaling components, reduce GLUT4
gene transcription, or alter mitochondrial activity [19
]. Mechanisms, such as oxidative stress that is associated with hyperglycemia, lipotoxicity, and glucotoxicity are also responsible for the development of IR in T1DM. Oxidative stress causes an increase in the production of pro-inflammatory cytokines and, thus, the induction of inflammatory processes. In T1DM immune cells, such as macrophages, which are the source of pro-inflammatory cytokines, migrate to pancreatic islet cells. Chronic inflammation can also be included among the factors that contribute to the development of IR in T1DM. Adipose cell enlargement leads to a pro-inflammatory state and the formation of pro-inflammatory compounds, such as interleukin-6, C-reactive protein, and plasminogen activator inhibitor-1, which, in turn, contribute to the death of β-cells, modulation of β-cell regeneration processes, and IR [20
]. Studies conducted by Gunawardana and Piston [22
] seem to be in line with that notion. The authors investigated therapeutical effects of embryonic BAT (brown adipose tissue) transplants on the reversal of STZ- (streptozotocin) and autoimmune-mediated T1DM. The team was able to improve whole body glucose metabolism in mice. They attributed the success to the post-transplant increased the level of plasma insulin-like growth factor-I (IGF-I), a hormone with well-known anti-inflammatory properties [22
The development of IR is also related to the gender of T1DM patients. Millstein et al. found that T1DM affected adipose and skeletal muscle insulin sensitivity to a greater extent in women than in men [25
]. Participants in the control groups presented higher Morbus values (M-values) than those with DM, regardless of gender. Interestingly, women had a higher M-value than men from the respective control groups, whereas there were no differences by sex in M-values among the participants with T1DM. This result may suggest a greater deficit in the whole-body insulin sensitivity in women than in men with T1DM. Additionally, during the third stage of the glucose uptake study, some differences were observed for the values between women with and without T1DM [25
]. During the first and second stages of the hyperinsulinemic-euglycemic clamp, the difference in FFA concentration by T1DM status was greater in women than in men during the least-squares means stages. These changes in IR in skeletal muscle and adipose tissue may be associated with disturbances in the hypothalamic-pituitary-gonadal axis in T1DM [25
The severity of IR is variable and it depends on the influence of many factors. It is also related to the duration of T1DM [27
]. A family history of T2DM has also been shown to be associated with greater IR in T1DM [27
]. IR, as measured by the estimated glucose disposal rate (eGDR), is greater in racial/ethnic minorities as non-Hispanic blacks, Hispanics than in non-Hispanic whites [33
A decreased insulin response is reported in adolescence when hormonal changes are observed, mainly in the growth hormone and sex hormones levels. It is often said that growth hormone has an anti-insulin effect because it impairs the ability of insulin to stimulate glucose uptake in peripheral tissues and enhances hepatic glucose synthesis. Growth hormone secretion is pulsatile throughout the day, but almost 50% of the daily secretion of this hormone occurs during the night. The dawn phenomenon happens as a result of increased blood glucose levels in the early morning hours (between 3 and 5 am) and it results in a significant increase in glucose levels on awakening. Physiologically speaking, between these hours the insulin level drops, which results in unblocking growth hormone secretion. A healthy person has a compensating mechanism in the form of additional insulin release, in people with DM this mechanism is disturbed, which leads to the appearance of pathology in the form of the dawn phenomenon. This event is most often observed in patients with T1DM, especially in children in their puberty period. It is related to the increased secretion of growth hormone by the pituitary gland during the night [35
However, in adults, growth hormone deficiency may occur. It manifests itself by increased visceral obesity, IR, dyslipidemia, and hyperglycemia, and it contributes to increased cardiovascular morbidity and mortality. Insulin-like growth factor (IGF-1), which, like insulin, reduces blood glucose level, has anti-inflammatory properties, and it is important for the regulation of glucose uptake by peripheral tissues [36
Growth hormone therapy has an antagonistic effect on insulin with respect to peripheral tissues, such as the liver, skeletal muscle, and adipose tissue. It increases glucose uptake by skeletal muscle and the liver and reduces it in adipose tissue. To compensate for the increase in circulating glucose level, following the administration of growth hormone, insulin production increases. As a result of growth hormone supplementation, an increase in lipolysis in visceral adipose tissue is observed, which leads to an increased number of FFA in the blood, which, in turn, causes the disruption of insulin signaling pathway and directly exerts toxic effect on β-cells [36
Increased IR may be due to the presence of autoantibodies, i.e., antibodies against endogenous insulin and/or antibodies that are directed against the insulin receptor [37
]. In case of some patients undergoing insulin therapy, the antibodies are produced against exogenous insulin [38
]. This situation increases the risk of allergic reactions, large fluctuations in blood glucose levels, and increased insulin requirement.
IR severity/presence can be estimated by the: oral glucose tolerance test, the HOMA method for calculating the IR index (HOMA-IR), and the hyperinsulinemic-euglycemic clamp methods.
Metformin is a drug of choice in T2DM due to its safety and efficacy, as well as its multi-metabolic effects. Not only does it lower glycemic stability by sensitizing tissues to the impact of insulin, but it also increases glucose uptake by adipose tissue and supports the process of FFA re-esterification. Through these processes, it prevents lipolysis and the release of FFA to the blood. This drug increases the activity of lipoprotein lipase, lowers the concentration of triacylglycerol, as well as total and LDL cholesterol. It also has anti-inflammatory and antioxidant properties.
Many studies have been conducted on the appropriateness of introducing metformin to the pharmacotherapy of patients with T1DM. The results indicated that these patients obtained an improvement in total insulin dose, basal insulin dose, a modest reduction in weight, or lipids level (total and LDL cholesterol), but only during short term observation [64
]. Some studies also confirmed that metformin may lower HbA1c level [65
]. The above-mentioned positive effects are no longer observed with long-term drug supplementation. During many years of research, no significant changes in body weight, total daily insulin dose, basal insulin dose, improvement in lipids level, or fasting plasma glucose or HbA1c level were observed in the patients [67
]. Some studies also indicated the possible side effects of metformin application, such as an increased risk of adverse gastrointestinal effects [64
]. Some studies also report vitamin B12 deficiency in patients with T1DM [66
]. For patients with T1DM, this vitamin is important due to the reduction of the high homocysteine level, which is considered to be a major risk factor for the formation of atherosclerotic plaque. Vitamin B12 also participates in the formation of myelin sheaths of neurons, which are necessary for the process of nerve impulses conduction [73
]. Its deficiency can lead to nerve damage.
Metformin is successfully used for the treatment of people with T2DM; however, not much is known regarding its impact on T1DM. A longitudinal study conducted by Staels et al. that encompassed 10 years timespan proved the lack of long-term beneficial effects of metformin therapy on weight loss, HbA1c level reduction, or diminishing insulin dosage requirements. Therefore, this drug is not expected to bring satisfactory effects, even after a long-term pharmacotherapy of patients with T1DM [68
An ideal drug should meet several criteria, as Drzeworski emphasized. First of all, it should reduce IR in T1DM and protect β-cells, and, thus, reduce the need for insulin. Secondly, it should also reduce hyperglycemia, body weight, oxidative stress, and the risk of cardiovascular complications that stem from many years of its administration [74
]. Important features of the ideal drug also include: its affordable price, high safety, improvement of the patient’s life quality, and extension of its duration. Although metformin meets many of these criteria, future studies in search for an ideal medication for IR in T1DM are still warranted [75
However, we should remember the words of the doctor of medicine, the court physician of Polish kings, Wojciech Oczko, who often repeated that “Movement can replace almost any medicine, but all medicines taken together can’t replace movement”.