Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

Metabolic disorders and diabetes (DM) impact more than five hundred million individuals throughout the world and are insidious in onset, chronic in nature, and yield significant disability and death. Current therapies that address nutritional status, weight management, and pharmacological options may delay disability but cannot alter disease course or functional organ loss, such as dementia and degeneration of systemic bodily functions. Underlying these challenges are the onset of aging disorders associated with increased lifespan, telomere dysfunction, and oxidative stress generation that lead to multi-system dysfunction. These significant hurdles point to the urgent need to address underlying disease mechanisms with innovative applications. New treatment strategies involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are dependent upon programmed cell death pathways, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide, and growth factor applications. Non-coding RNAs, Wnt signaling, and AMPK are cornerstone mechanisms for overseeing complex metabolic pathways that offer innovative treatment avenues for metabolic disease and DM but will necessitate continued appreciation of the ability of each of these cellular mechanisms to independently and in unison influence clinical outcome.


The Impact of Metabolic Disorders in the Global Population
It is estimated that by the year 2045, almost eight hundred million individuals will suffer from metabolic disorders with the greatest majority of these individuals having diabetes mellitus (DM) [1].These observations suggest that almost one in eight people will have DM, and this represents a fifty percent increase from the current prevalence of metabolic disorders.Presently, there are approximately five hundred thirty-seven million people with DM, and these numbers will increase to more than six hundred forty million individuals by the year 2030 [2][3][4][5][6].Almost seventy-five percent of adults currently suffer from DM in predominately low-and middle-level income nations [1,7,8].At least two million deaths a year from DM occur in relatively young people less than seventy years old [5,[8][9][10][11][12] (Table 1).

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Metabolic disorders and diabetes mellitus (DM) are insidious in onset, progressive in nature, chronic in duration, and are expected to impact one in eight individuals, and over USD eight billion are necessary on an annual basis to meet clinical needs.
• Multiple factors can influence the development of metabolic disorders and DM, including increased weight with obesity, lower education levels, socioeconomic status with limited health resources, and increased lifespan with age-related disease, telomere dysfunction, cellular senescence, generation of reactive oxygen species (ROS), and tissue and organ degeneration.
• Given that current therapies for metabolic disease and DM are not curative for these disorders, innovative treatment avenues are required that involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are linked to programmed cell death pathways, oxidative stress, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide, and growth factor applications.
• Non-coding RNA pathways with miRNAs and circRNAs play a central role in the oversight of programmed cell death pathways, Wnt signaling, WISP1, and AMPK to offer mechanisms for pancreatic β-cell protection, reduction in inflammatory pathways, maintenance of mitochondrial integrity, promotion of insulin secretion, reduction in insulin resistance, and enhancement of cellular survival.
• Yet, detailed insight into non-coding RNA and related pathways is critical for the development of future clinical applications since these pathways are intimately linked to one another, have complex autofeedback systems, and can sometimes lead to detrimental outcomes such as the destruction of pancreatic β-cells, loss of glucose homeostasis, and distant systemic organ effects, such as excessive amyloid deposition in the brain.
In addition to the broad range of disorders that can result from metabolic disease, a significant financial burden to address metabolic disorders also is a recognized burden for both individuals and nations.The necessary finances to provide care for DM are increasing and presently estimated at USD seven hundred sixty billion [1].An additional USD seventy billion is believed to be required for patients with significant disability.As a result, DM care consumes more than seventeen percent of the United States (US) gross domestic product [96].At the individual level, every year USD twenty thousand is required to assist with glucose monitoring, infections, care coaching, and treatment for wounds [5,9,27,33,36,38,40,89,[97][98][99][100][101]].Yet, these numbers do not fully grasp the overall financial requirements for metabolic disease and DM.Worldwide, four hundred million people currently have DM or are at significant risk of acquiring DM [1,59,102].More than seven million individuals may suffer from DM but remain undiagnosed.In addition, over thirty-five percent of people in the US may be pre-diabetic with elevated fasting glucose and hemoglobin A1c (HbA 1c ) levels but are not currently under treatment [8,103].

Lifespan, Aging, Obesity, and Socioeconomic Status Can Impact Metabolic Disorders
Multiple factors can affect the development of metabolic disorders and DM, including increased lifespan and age of the population, lower levels of physical activity, increased weight with obesity, education level, and socioeconomic status (Table 1).Throughout the world, lifespan has been increasing to the extent that most individuals will reach at least eighty years of age [104][105][106][107][108][109][110].Individuals in developing nations are expected to experience a rise in the number of those over the age of sixty-five to increase by ten percent, and in developed nations, individuals over the age of sixty-five have more than doubled over the prior fifty-year period [106,111].A number of considerations have led to improved lifespan, including improved sanitation and environmental measures, early access to healthcare, broader public healthcare policies, and more effective nutrition programs [104,[112][113][114].However, with the increase in lifespan comes the effects of aging and degenerative processes.The onset of cell senescence and degeneration of tissues can occur with DM and metabolic dysfunction [2][3][4]41,79,82,115,116].Destabilization of telomeres (TLs) through processes of shortening ultimately leads to cellular senescence [117][118][119][120]. Factors that involve increased lifespan (>80 years of age, improved care), aging, increased weight with obesity, lower education level, and socioeconomic status can have significant roles in the development of diabetes mellitus (DM) that affects 537 million (M) individuals.With aging-related disease, the destabilization of telomeres (with genomic degradation, senescence, and cell growth arrest) through processes of shortening ultimately leads to cellular senescence, oxidative stress (release of reactive oxygen species (ROS), and the degeneration of tissues and organs (with immune and organ repair dysfunction).In addition, other conditions that can be influenced by socioeconomic conditions (low income and increased cortisol levels) include elevations in serum cholesterol, high blood pressure, and tobacco use (insulin resistance and cardiac and vascular degeneration).A low level of education (a lack of knowledge of symptoms, care, and disease complications) and in-address underlying disease mechanisms.Novel considerations for the development of new strategies for metabolic disorders and DM involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are intimately tied to agingrelated disease, oxidative stress, programmed cell death pathways, cellular metabolic avenues with AMP-activated protein kinase (AMPK) and nicotinamide, and trophic factor considerations (Figure 2).New treatment strategies for metabolic disease and diabetes mellitus with non-coding RNAs.Non-coding RNAs play a central role in the oversight of complex metabolic pathways that offer innovative treatment avenues for metabolic disease and diabetes mellitus (DM).Innovative considerations involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are dependent upon programmed cell death pathways, such as apoptosis and the externalization of membrane phosphatidylserine (PS) residues on cell membranes, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+) pathways with nicotinamide, and growth factor applications.These pathways intersect with one another for new therapeutic strategies, such as controlling microglial activation and limiting reactive oxygen species (ROS) generation.Microglia can be detrimental to the release of reactive oxygen species (ROS) to generate oxidative stress but also can be beneficial for the clearance of toxins (amyloid) in the brain and the reduction of inflammation.Importantly, microglial pathways are overseen by Wnt  New treatment strategies for metabolic disease and diabetes mellitus with non-coding RNAs.Non-coding RNAs play a central role in the oversight of complex metabolic pathways that offer innovative treatment avenues for metabolic disease and diabetes mellitus (DM).Innovative considerations involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are dependent upon programmed cell death pathways, such as apoptosis and the externalization of membrane phosphatidylserine (PS) residues on cell membranes, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+) pathways with nicotinamide, and growth factor applications.These pathways intersect with one another for new therapeutic strategies, such as controlling microglial activation and limiting reactive oxygen species (ROS) generation.Microglia can be detrimental to the release of reactive oxygen species (ROS) to generate oxidative stress but also can be beneficial for the clearance of toxins (amyloid) in the brain and the reduction of inflammation.Importantly, microglial pathways are overseen by Wnt signaling and erythropoietin (EPO).Triggering receptor expressed on myeloid cells 2 (TREM2) is vital to foster microglial survival to prevent inflammation.In addition, metformin, as well as trophic factors with EPO, as examples of new therapeutic strategies, can reduce metabolic dysfunction and assist with the treatment of dementia, cardiovascular disease, multiple sclerosis, and peripheral neuropathy through the oversight of microglia, AMPK (maintains mitochondrial function), and non-coding RNA pathways.
CircRNAs consist of non-coding RNAs of approximately 100 nucleotides [100,142,152,313,316,329,[333][334][335][336]414,419,432,[440][441][442][443][444][445].First identified as having a circular structure, circRNAs use covalent bonds to maintain a circular nature, contain both cis and trans regulation, oversee the expression of genes through the sponging of miRNAs [335,[446][447][448], and can have value as biomarkers [329, 335,429,432,436,449].In vascular and metabolic disease, atherosclerosis may be prevented through circular antisense non-coding RNA in the INK4 locus (circANRIL) in vascular smooth muscle cells and macrophages by blocking exonuclease-mediated pre-ribosomal RNA generation and cell proliferation [450].During periods of glucolipotoxicity in DM, circPIP5K1A can act as a sponge to reduce protective miRNA miR-552-3p and allow autophagy activation of pancreatic β-cells, suggesting that the down-regulation of circRNA circPIP5K1A can be a target for disease treatment [316].As another example of potential detrimental outcomes with circRNAs, circRNA expression can reduce beneficial miRNA expression and yield excessive amyloid production in the brain [431] by down-regulating protective pathways of the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) [27,131,231,[451][452][453][454][455]].Yet, applications with circRNAs also can have a beneficial outcome.Treatment with the circRNA CiRS-7 as a sponge for the miRNA miR-7 can promote insulin secretion and prevent the onset of DM [456].Targeting circRNA also may be vital for the treatment of diabetic retinopathy [74], functioning as biomarkers for cardiovascular DM disease [100] and overseeing mTOR pathways with PRAS40 [53,335].
WISP1 is a downstream component of wingless signaling with Wnt proteins and a member of the CCN family of secreted extracellular matrix-associated proteins, six in number, that are termed by the first three members of the family that include cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed genes [14,27,299,485,486].Similar to the Wnt1 signaling pathway, WISP1 can control the stability and progression of atherosclerotic vascular plaques [296], decrease through Akt pathways lipopolysaccharideinduced injury of cells [297], alter blood-brain barrier disease [485], protect neuronal survival [487,488], and limit oxidative stress [106,489,490].During metabolic disease and DM, WISP1 is a marker of adipose tissue inflammation [491].It is involved in pancreatic regeneration during glucose homeostasis [492] and can foster pancreatic β-cell development [493].During periods of loss of glucose homeostasis, WISP1 may be protective since it is elevated during gestational DM [150,494] and has higher serum levels and insulin resistance in obese children and young adolescents [150,495,496] (Table 1).
WISP1 modulates metabolic cellular pathways through AMPK and also has feedback mechanisms with itself and miRNAs.AMPK can assist with energy metabolism and lead to the production of adenosine triphosphate (ATP), which may influence sensory nerve function.For example, pain during DM with peripheral neuropathies can be relieved by AMPK activation in experimental models [497].In addition, nicotinamide relies upon AMPK to preserve mitochondria function [261], and Wnt family members employ AMPK to limit neuronal injury [498].AMPK can maintain electrical activity of the cortex for behavior control [499], AMPK oversees endothelial tight junctions [500], and AMPK can promote mitochondrial integrity during ferroptotic cell death [169].In the absence of AMPK activity, cell senescence, cell death, and mitochondrial injury can ensue [3,137].WISP1 controls the phosphorylation of AMPK by differentially limiting phosphorylation of tuberous sclerosis 2 (TSC2) at serine 1387 , a target of AMPK, and promoting phosphorylation of TSC2 at threonine 1462 , a target of Akt [103,300,310,345,396,490,501] that has been shown to mediate protection of pancreatic cells [502] and neuroprotection [60,455,503] through glucagon-like peptide-1 (GLP-1).This ability of WISP1 to target and control AMPK may improve cell survival and metabolic homeostasis [168] since AMPK at times can reduce oxidative stress, limit insulin resistance [369], and lower lipid accumulation [504].Yet, AMPK has another side requiring close regulation since under other circumstances, AMPK may lead to cell demise with autophagy [8,505,506].In addition, non-coding RNAs can indirectly control WISP1, signaling the modulation of AMPK.AMPK is independently linked to miRNAs and can control miRNA expression, such as miR-185, to offer cellular protection through the up-regulation of miR-185 [425].Furthermore, miRNAs, such as miR-185, can suppress AMPK and autophagy activity to lead to increased cell survival and block apoptosis [425].Under conditions with growth factors, such as EPO, Cells 2023, 12, 2595 10 of 33 AMPK activity must be regulated to limit oxidative stress [490] and inflammation [306,507] since the elevated activity of EPO and AMK can result in cell injury [508].EPO can modulate AMPK activity [27,[509][510][511][512].Interestingly, WISP1 can control its own expression through autophagy and apoptotic pathways [513].In addition, WISP1 can be regulated through potential feedback mechanisms involving miRNAs, such as miR-515-5p and miR-128-3p, to have WISP1 expression reduced [305,307] for improved glucose homeostasis.In other considerations with WISP1, the down-regulation of WISP1, either through the direct control of non-coding RNAs or through non-coding RNAs using AMPK, may be a potential therapeutic target to limit tumor growth [514], an important consideration for the trophic pathways of Wnt signaling and WISP1 that can promote tumorigenesis [76,130,337,457,461,462,470,515,516].

Conclusions and Future Perspectives
Metabolic disorders and DM are chronic diseases that affect a significant number of individuals in the global population.It is expected by the year 2030, more than 640 million individuals will be affected by DM, and the greatest proportion of these individuals reside in low-and middle-income nations.Financial considerations to care for individuals with metabolic disease are equally staggering and can exceed USD seven hundred billion with at least USD twenty thousand required annually for every patient to provide minimum care including glucose monitoring, nutritional coaching, and treatment of infections and wounds.Yet, these challenges may not provide the complete picture since more than four hundred million people may remain currently undiagnosed with either pre-diabetes of DM and have elevated fasting glucose and HbA 1c levels.
DM affects all systems of the body and can lead to renal failure, liver disease, neurodegeneration with cognitive loss, and cardiovascular disease.Furthermore, metabolic disorders and DM are chronic and progressive in nature that lead to severe disability and death.Underlying these conditions are the effects of aging, increased weight gain, and additional risk factors that can be tied to socioeconomic status.With the observed increase in global lifespan, the consequences of aging in the presence of metabolic disease and DM can involve TL dysfunction, the onset of cellular senescence, and organ and tissue degeneration.Accompanying these processes are the increased risk of obesity that leads to immune system dysfunction, infection susceptibility, such as with SARS-CoV-2 and COVID-19, loss of mitochondrial integrity, and the generation of oxidative stress.Lower socioeconomic status compounds these complications for the development of DM, which include low education status and inadequate nutritional care.Current therapies for DM attempt to address these risk factors with access to proper nutritional education and weight management that are accompanied by pharmaceutical agents to manage insulin release and resistance as well as overall glucose homeostasis.Yet, these strategies do not halt overall disease progression and can lead to disability with periods of hypoglycemia or hyperglycemia.These therapies also may lead to decreased cell survival in multiple organs, promote the degeneration of organs, and may have no effect on the progression of disorders involving cognitive loss in the central nervous system and nerve degeneration in the peripheral nervous system.Such considerations demand innovative clinical strategies to address the underlying mechanisms of metabolic disorders and DM that involve non-coding RNA pathways with miRNAs and circRNAs, Wnt signaling, and WISP1.These pathways are intimately tied to the generation of aging pathways, ROS, and oxidative stress and can function through programmed cell death mechanisms, metabolic pathways involving AMPK and nicotinamide, and trophic factor applications.
Oxidative stress is a critical pathway in the pathology of metabolic disorders and DM.The release of ROS can lead to the death of multiple cell types, which can affect neurons, vascular cells, stem cells, and musculoskeletal cells.The presence of intrinsic and extrinsic anti-oxidant systems can offer a vital aide to potentially prevent both the onset and progression of DM.Nicotinamide can be an important component of these anti-oxidant systems, especially as a precursor for NAD + , offering the ability to maintain cellular metabolic homeostasis.Nicotinamide can be effective against oxidative stress and offer cellular pro-tection at a number of levels in the apoptotic death cascade, which include maintenance of mitochondrial membrane potential, reduced activity of inflammatory pathways, limited muscle degeneration, and assistance with insulin resistance.Yet, concentrations of cellular nicotinamide should always be considered since elevated levels of nicotinamide can decrease SIRT1 activity [517] and may conceivably reduce protection for cells during oxidative stress through the loss of SIRT1.In addition, elevated concentrations of nicotinamide can lead to decreased cell survival through other means.
The pathways of programmed cell death are also important targets for the treatment strategies of metabolic disorders and DM.Therapies that can address early phases of apoptosis during membrane PS residue externalization can be reversible and could protect impaired pancreatic β-cells, prevent retinal cell disease and neurodegeneration, control activation of inflammatory cells, such as microglia, and protect against cardiovascular disease.The use of proteomics also may assist with the investigation of these pathways with apoptosis, which examines the function and cellular activities of proteins at the cellular level.For example, the understanding of intracellular and extracellular apoptotic protein bodies can provide insight into metabolic, neurodegenerative, aging, and cancer pathways [50,304,[518][519][520][521].Autophagy is closely tied to apoptotic pathways and can limit retinopathy during DM, foster the processing of circulating oxidized fatty acids, maintain mitochondrial integrity, especially during exercise, oversee the development and function of pancreatic β-cells, and preserve memory function.However, the modulation of autophagy pathways requires a careful balance since clinical strategies that incorporate autophagy for glucose homeostasis can ultimately, if left unchecked, lead to loss of organ mass, atherosclerosis development, decreased interneuron progenitor cell survival, neuronal cell death, mitochondrial dysfunction, and cognitive loss.In addition, serum glucose fluctuations can promote inflammatory pathways mediated by autophagy that result in apoptotic cell death and also activate mechanisms of pyroptosis and ferroptosis.Growth factors, such as EPO, also require the down-regulation of autophagy pathways for neuronal and vascular protection in DM.
Interestingly, programmed cell death pathways work in conjunction with non-coding RNAs, Wnt signaling, and WISP1.The activation of autophagy is necessary for the function of circRNAs in the modulation of oxidative stress, inflammatory activation, and the secretion of insulin.In fact, non-coding RNAs are involved with almost all types of programmed cell death pathways, including apoptosis, autophagy, ferroptosis, and pyroptosis.Both microRNAs and circRNAs can limit oxidative stress and inflammation, oversee insulin secretion, act as biomarkers, and prevent atherosclerotic disease.Depending on the specific nature of the non-coding RNA and the relationship between microRNAs and circRNAs functioning as sponges, either enhanced cellular survival can be fostered or detrimental outcomes may result, such as the excessive deposition of amyloid in the brain.Studies are employing regularly interspaced palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) technology to further elucidate the role of non-coding RNAs [444], inflammation [522], and Wnt signaling [485,522] in experimental models.For these reasons, the role of Wnt signaling and WISP1 becomes critical since non-coding RNAs can modulate the function of these pathways.Wnt signaling and WISP1 offer a number of protective outcomes during metabolic disease and DM, including controlling programmed cell death pathways, overseeing glucose homeostasis through AMPK-mediated pathways, limiting oxidative stress generation, promoting vascular cell integrity and reducing atherosclerosis, fostering pancreatic regeneration and pancreatic β-cell development, and assisting with insulin resistance.However, Wnt signaling and WISP1, as strong trophic-based pathways, can promote tumorigenesis.As a result, oversight of Wnt signaling and WISP1 through non-coding RNAs becomes a critical element as an essential feedback mechanism in these pathways when considering clinical applications for the treatment of metabolic disease and DM.In addition, non-coding RNAs can indirectly regulate WISP1 signaling through AMPK to either control the activity of AMPK or promote the ability of AMPK to control miRNA expression and activity.
It is also important to note the direction of current and future strategies of treatment for these pathways for metabolic disorders, including pharmaceuticals, cell-based therapies, and biological factors.In this regard, AMPK pathways are central to present agents to treat DM; they include metformin and biguanides to reduce the effects of neurodegenerative and vascular disease.These include therapies for dementia, cardiovascular disease, multiple sclerosis, and peripheral neuropathy [2,42,59,71,172,240,523,524].Metformin can reduce metabolic dysfunction and lipid peroxidation in the brain and spinal cord by reducing caspase activity to promote the survival of cells [525].Metformin also controls glucolipid metabolism [159], reduces aging-related disorders [4,5], limits inflammation [111,252,359,526], and blocks TOR activity to increase autophagy induction, and it may provide increased cell survival at times independent of AMPK [527].Metformin is being considered for other disease applications, such as limiting disability in patients with obesity or individuals with DM during coronavirus disease 2019 (COVID-19) [42,70,71,[170][171][172], as well as increasing the recovery of myelin in experimental models of multiple sclerosis [523].Of note, metformin is vital for the control of non-coding RNAs as well.It has been shown that miR-34a up-regulation can lead to endothelial dysfunction during oxidative stress and DM.Yet, this disease process can be modulated by metformin to oversee miR-34a and foster vascular protection.Microglia also represent an emerging target for therapy in metabolic disease.Microglia are vital for removing injured cells, especially those tagged by membrane PS externalization, but careful modulation of these inflammatory cells is important since on one hand, they can lead to the production of ROS and oxidative stress that can result in the loss of metabolic homeostasis.Yet, on the other hand, microglia can assist with the removal of toxins, such as amyloid, and preserve cholesterol homeostasis with autophagy.Through pathways that are dependent upon TREM2, new therapies using microglia are being considered to improve cognition, reduce memory loss, block inflammation, and be important tools for identifying metabolic disease progression.The therapeutic pathways that oversee microglia function are intimately tied to non-coding RNAs that oversee inflammatory pathways [251,[332][333][334][335][336], Wnt signaling, and growth factors, such as EPO.Growth factors, such as EPO, are also being seen as necessary to control AMPK and non-coding RNA pathways.Independently, pathways, such as Wnt signaling and WISP1, are now being considered biomarkers for the risk of gestational DM and tissue inflammation in DM.In summary, non-coding RNAs with miRNAs and circRNAs have a vital oversight of each of these complex metabolic pathways, which involve aging processes, oxidative stress, programmed cell death pathways, Wnt signaling, WISP1, AMPK, and cellular metabolism pathways and can involve nicotinamide and trophic factors.As a result, non-coding RNAs, Wnt signaling, and AMPK offer exciting considerations for the future development of innovative strategies for metabolic disorders, but a further appreciation of the multifarious relationship among these cellular pathways is necessary for the effective execution of clinical care.

Figure 1 .
Figure 1.Multiple factors can influence the development of metabolic disease and diabetes mellitus.Factors that involve increased lifespan (>80 years of age, improved care), aging, increased weight with obesity, lower education level, and socioeconomic status can have significant roles in the development of diabetes mellitus (DM) that affects 537 million (M) individuals.With aging-related disease, the destabilization of telomeres (with genomic degradation, senescence, and cell growth arrest) through processes of shortening ultimately leads to cellular senescence, oxidative stress (release of reactive oxygen species (ROS), and the degeneration of tissues and organs (with immune and organ repair dysfunction).In addition, other conditions that can be influenced by socioeconomic conditions (low income and increased cortisol levels) include elevations in serum cholesterol, high blood pressure, and tobacco use (insulin resistance and cardiac and vascular degeneration).A low level of education (a lack of knowledge of symptoms, care, and disease complications) and increased weight and obesity (pancreatic cell loss and inflammation) also impact DM.

Figure 2 .
Figure 2.New treatment strategies for metabolic disease and diabetes mellitus with non-coding RNAs.Non-coding RNAs play a central role in the oversight of complex metabolic pathways that offer innovative treatment avenues for metabolic disease and diabetes mellitus (DM).Innovative considerations involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are dependent upon programmed cell death pathways, such as apoptosis and the externalization of membrane phosphatidylserine (PS) residues on cell membranes, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+) pathways with nicotinamide, and growth factor applications.These pathways intersect with one another for new therapeutic strategies, such as controlling microglial activation and limiting reactive oxygen species (ROS) generation.Microglia can be detrimental to the release of reactive oxygen species (ROS) to generate oxidative stress but also can be beneficial for the clearance of toxins (amyloid) in the brain and the reduction of inflammation.Importantly, microglial pathways are overseen by Wnt

Figure 2 .
Figure 2.New treatment strategies for metabolic disease and diabetes mellitus with non-coding RNAs.Non-coding RNAs play a central role in the oversight of complex metabolic pathways that offer innovative treatment avenues for metabolic disease and diabetes mellitus (DM).Innovative considerations involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are dependent upon programmed cell death pathways, such as apoptosis and the externalization of membrane phosphatidylserine (PS) residues on cell membranes, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+) pathways with nicotinamide, and growth factor applications.These pathways intersect with one another for new therapeutic strategies, such as controlling microglial activation and limiting reactive oxygen species (ROS) generation.Microglia can be detrimental to the release of reactive oxygen species (ROS) to generate oxidative stress but also can be beneficial for the clearance of toxins (amyloid) in the brain and the reduction of inflammation.Importantly, microglial pathways are overseen by Wnt signaling and erythropoietin (EPO).Triggering receptor expressed on myeloid cells 2 (TREM2) is vital to foster microglial survival to prevent inflammation.In addition, metformin, as well as trophic factors with EPO, as examples of new therapeutic strategies, can reduce metabolic dysfunction and assist with the treatment of dementia, cardiovascular disease, multiple sclerosis, and peripheral neuropathy through the oversight of microglia, AMPK (maintains mitochondrial function), and non-coding RNA pathways.

Table 1 .
Highlights of implementing strategies for non-coding RNAs with microRNAs and circular RNAs in metabolic disorders and diabetes mellitus.