ReviewNanomedicine for treatment of diabetes in an aging population: State-of-the-art and future developments
Introduction
The importance of nanomedicine to face the challenges imprinted on the society by an aging population to guarantee high life quality and health was recently highlighted in an editorial by Gabellieri and Frima [1]. While in this editorial they focused on the impact nanomedicine can have on treatment of neurodegenerative diseases the same holds true for other age-related disease such as diabetes with its world-wide epidemic spreading.
Diabetes mellitus (DM) is a disease which has become epidemic in the world, which is reflected by the fact that the total number of patients with DM is expected to rise from 171 million in 2000 to prognosticated 366 million in 2030 based on the data from 40 countries published by the WHO [2]. DM continues to increase in prevalence and impact. This causes an excess in healthcare expenditure, and finally a large economic burden through loss of productivity and foregone economic growth [3].
To complicate the picture many will not suffer from just one disease; they will, on average, be managing up to five co-morbidities by the age of 65 [4]. This does not include the side effects of diabetes, such as blindness due to diabetic retinopathy, or the complications of insulin management with multiple drugs to control cardiovascular disease. The burden to society is not caused by the disease, but the result of the complications of the disease when it is uncontrolled. Though the management of diabetes is now straight forward, before injectable insulin it was a death sentence. With many of the new control procedures people will live a long and relatively healthy life. With this we are starting to see long term consequences of disease that did not exist in the past because most diabetics did not live beyond their 60th year. Now there is no reason they cannot live into their 100s.
The two major forms of diabetes are type 1, an autoimmune-mediated destruction of pancreatic islet beta-cells and type 2 diabetes mellitus (T2DM) [3], [5]. It is in particular incidence of T2DM that has exploded over the last decades owing to an aging population in the developed world as well as a changed life-style and adaption to western nutrition in developing countries [6], [7]. The reasons for T2DM are not completely understood but seem to be closely related to physical inactivity and the resulting obesity [8]. In the past T2DM was a disease which occurred more often in the elderly and one of the bodily changes related to aging is a progressive increase in body fat [8]. Metabolically T2DM is due to an insufficient insulin secretion to cope with the increased blood glucose level [9] as well as the presence of insulin resistance. However, beta cell failure is the crucial factor, due to reduced beta cell mass and functional beta cell defects [10], [11].
More recent findings indicate that among the chain of events leading to the impairment of insulin secretion, some might be targeted by nanomedicine. Many changes at the gene and protein expression levels have been reported in type 2 diabetic pancreatic islets. Using oligonucleotide microarrays of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls, it has been found that 370 genes were differently expressed in the two groups [12]. Quantitative RT-PCR studies were performed in the same study, showing changes in the expression of genes known to be important in beta-cell function, including major decreases in the expression of HNF4alpha, insulin receptor, IRS2, Akt2, the transcription factor ARNT/HIF1beta (hydrocarbon nuclear receptor translocator/hypoxia-inducible factor 1β) and several glucose-metabolic-pathway genes. Successively, several genes encoding for the following proteins were found to be downregulated in type 2 diabetic islets by real-time RT-PCR: insulin, glucose transporter 1, glucose transporter 2, glucokinase, and molecules involved in insulin granules exocytosis [13], [14]. On the contrary, genes implicated in differentiation and proliferation pathways have been reported to be increased in diabetic islets, including PDX-1, Foxo-1, Pax-4, and TCF7L2 [13], [15], [16]. Furthermore, changes at the level of the expression of genes involved in regulating cell redox balance have been shown [17].
Some information is also available as for protein expression in type 2 diabetic islets. The amount of insulin has been reported to be decreased 30–40% in diabetic islet cells [13], [14]. The expression of AMP-activated kinase, IRS-2, PDX-1 (this latter at odds with gene expression data), and that of proteins involved in exocytosis was also found to be decreased in type 2 diabetic islets in comparison to non-diabetic samples [13], [14]. In addition, TCF7L2 protein expression was also found to be decreased in type 2 diabetic islets [18]. Interestingly, some data are available on type 2 diabetic islet protein profiling, as reported recently [19]. The data showed that in islets isolated from type 2 diabetic individuals the most activated pathways were pathways of cell arrest and apoptosis (p53, caspase, stress-activated).
Increased deposition of islet amyloid polypeptide (IAPP) in the islets could also contribute to beta cell dysfunction and death [20]. High concentrations of IAPP cause aggregation, fibril formation and eventually islet amyloidosis [20]. Recent evidence favours the concept that it is the process of amyloid fibril formation or the formation of toxic IAPP oligomers, rather than the deposit of mature fibrils, to be cytotoxic [11].
Other studies indicate an involvement of microRNAs in the development and prevalence of T2DM [21]. MicroRNA is a recently discovered group of non-coding but regulatory single-stranded RNAs of around 22 nucleotide length. They regulate gene expression by silencing, either by cleaving or repression, and target mRNA in a highly specific manner [21].
Recent findings showed that microRNA is involved in the process of glucose homeostasis in form of a “ribo-regulator” [22] and mainly inhibits the insulin exocytosis and alters the lipid metabolism, the link to obesity. A detailed description of the molecular mechanism of action can be found in the review article by Pandey and co-workers [21]. The profiling of the serum-derived microRNA seems to indicate in the direction of a novel class of biomarkers for the targeting of future generations of drug to diseased tissue [23]. A recently published work by Guay and collaborators is going in the same direction [24]. They studied T2DM and its effects on different diabetes affected tissues such as adipose tissue, liver and skeletal muscles in terms of differences in the microRNA profile. Moreover they clearly state that the changed microRNA profile is also reflected in the blood and hence can provide biomarkers to monitor onset [25] and development of T2DM [24]. Guay et al. [24] finally concluded that the microRNA can be a possible target for a gene-therapy curing type 2 diabetes.
In another work, Ohtsubo et al. [26] found that elevated levels of free fatty acids especially the palmitic acid lead to the nuclear exclusion and reduced expression of two transcription factors, connected to a specific glycosyltransferase responsible for the proper inclusion of the glucose transporter-2 into the beta-cell membrane and hence a loss of glucose-stimulated insulin secretion with all its consequences. The same pathway seems to be responsible for the increasing insulin resistance in the insulin target tissues such as liver, adipose tissue and skeletal muscles. They could show that an improvement of the conditions in terms of enforced glycosylation in the beta-cells leads to a general improvement also of the other insulin and glucose dependent tissues.
Why are we describing the reasons of T2DM in such detail? And what is changing with age? Because nanotechnology may provide the vehicles for targeted delivery of either siRNA, microRNA or DNA plasmids to correct insulin deficiency or novel drugs to dissolve diabetes related polypeptide amyloid fibers with strategies explored for beta-amyloid plaques in Alzheimer disease [27] or prion protein aggregates [28].
There are two great opportunities offered by nanomedicine, nanotechnology used for medical applications. One is the miniaturization of existing drug systems and to improve in this way the biocompatibility and bioavailability. The other is more groundbreaking. It uses nanomedicine for a sophisticated delivery of molecules which influences the disease origin rather than treating the symptoms and which never could be administered before. For the conventional medicine they were too valuable (low quantities available like hormones), too delicate (very fragile or immediate degradation like peptides or DNA), or too toxic (in larger quantities and untargeted delivery like toxins from animals). All these molecules now can be delivered with the new nanodrugs which require lower amounts of drugs, deliver preferentially only to the target organ or cell and protect the biological molecules during their travel throughout the body. But so far the nanomedicine for treatment of diabetes mellitus was used only to improve the existing administration forms of insulin and try to improve the life quality of DM patients by non-invasive administration and glucose monitoring.
Section snippets
Nanomedical approaches for non-invasive insulin substitution therapy
DM is associated with high morbidity and mortality, primarily mediated by the development of chronic vascular changes over time. In order to prolong the onset of these secondary symptoms a insulin replacement therapy is established standard treatment for the late-stage of T2DM as well as for type 1 diabetes. As the invasive multiple injections of precisely calculated amounts of insulin present a significant deterioration of the life quality of diabetic patients the first and best established
Conclusions
So far nanomedicine in the treatment of diabetes aims mainly to improve the life-quality of patients by providing a non-invasive insulin administration and glucose control. While the novel glucose detections systems promise a good opportunity to control the glucose level more frequently and hence allow a better insulin management the nanoparticulated insulin administration suffers mainly from its low bioavailability. It is to state that nanoparticles administered via the nasal or oral route
Outlook
So far few nanoparticle strategies were developed to target the intracellular accumulating human islet amyloid polypeptide (IAPP) and hence the IAPP induced beta-cell death which may be the reason for impaired insulin production in T2DM [60]. The first therapeutic approaches to inhibit the fibril formation of the IAPP by rifampicin failed leading to the conclusion that precursors such as oligomers are the cytotoxic form [11]. This can be a new approach for either the early diagnosis of the
Contributors
Silke Krol wrote the part about the nanoparticles and their interaction with the bio-interface.
Rutledge Ellis-Behnke wrote the part about the physiology in age and co-morbidities influencing NP uptake.
Piero Marchetti wrote the background information about diabetes and the cellular and genetic changes.
Competing interest
No competing interests.
Funding
S. Krol and P. Marchetti received a research grant from CariPisa.
Provenance of peer review
Commissioned and externally peer reviewed.
Acknowledgement
Piero Marchetti and Silke Krol are grateful by the financial support from CariPisa. Rutledge Ellis-Behnke thanks the Augenklinik, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg.
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