*2.5. Growth*

The pecking order theory states that there is a positive relationship between growth and debt. Companies with high growth rates need sufficient funds to support their investment opportunities and internal funds are unlikely to be enough to support them. Trade-off theory states that there is a negative relationship, assets intangibility of firms with high growth rates implies the risk of losing value in case of financial distress. (Chaklader and Chawla 2016; Psillaki and Daskalakis 2009) showed that the growth variable is statistically insignificant, contrary to (Alipour et al. 2015; Cortez and Susanto 2012) who concluded that the relationship between the growth variable and the dependent variable is significantly negative.

#### *2.6. Inflation*

Chadha and Sharma (2015) found that inflation is statistically insignificant. Bokpin (2009) obtained a significant relationship. In most cases, firms will resort to internal sources of financing during periods when inflation is high, as this pressure will increase the cost of obtaining capital from creditors.


**1. Introduction**

Bubble and drop dynamics in non-Newtonian fluids are a topic of undeniable interest within the community [1], owing largely to the number of real-world situations that may benefit from a comprehensive knowledge of the underlying physics: from drop formation mechanisms [2], to biomedical equipment involving droplet manipulation [3] or engineering devices in which breakup plays a central role [4,5], from droplet impact on liquid surfaces [6] to the study of drop dynamics within polymer gels and solutions [7,8]; a deeper understanding of this type of multiphase flows not only would improve existing manufacturing processes, but also encourage the development of new applications and spur breakthroughs in scientific research.

To study the multiphase flow of polymeric liquids, one should choose an appropriate discretization method capable of providing an accurate description of the interface. Mesh-based methods [9] offer such representation of the interface, either in an explicit (interface-tracking) or in an implicit (interface-capturing) form. Among the former, front-tracking and Arbitrary Lagrangian-Eulerian (ALE) schemes [10,11] display excellent performance in terms of mass conservation and shape preservation; however, remapping techniques are often found necessary [12] under extreme deformation of the moving interface. In contrast, interface-capturing methods follow a Eulerian approach, with the 'Volume-Of-Fluid' (VOF) method positioning itself as one of the most popular techniques within this context [13,14], showing good conservation properties, but requiring additional tools for handling geometrical quantities derived from the interface [15]. As an alternative, Level Set (LS) methods [16,17] capture the interface as the zero isocontour of a certain scalar function, which is advected by the flow, with noticeable mass loss and shape degradation if excessive diffusion is introduced during the advection stage. Despite these shortcomings, the LS method is widely used for interface problems undergoing dramatic deformation and topological changes and can be readily enhanced via "hybrid" schemes such as the Particle Level Set (PLS) method [18] that are able to ease, to a large extent, many of its drawbacks. Whatever the multiphase technique, the correct implementation of appropriate Boundary Conditions (BC) for the configuration of interest is a topic that requires careful consideration of the chosen discretization method [19], as it may have an enormous influence on the actual shape of the interface.

A common approach to handling the polymer interaction with the flow at a macroscopic scale is to represent the polymer contribution to the stress tensor by means of a closed-form, "constitutive" equation; thus, e.g., the work of Yue et al. [20–22] on drop deformation and complex two-phase flow using a diffuse-interface method and constitutive modeling; in [23], Pillapakkam employed an LS method to study rising bubbles in viscoelastic media, while Foteinopoulou and Laso [24] used a Phan–Thien-–Tanner model together with an elliptic mesh-deformation algorithm to investigate bubble oscillation; Castillo et al. proposed an LS method with a pressure-enriched FE space to study the two-fluid flow problem along with a Giesekus model for the polymeric liquid [25]; Fraggedakis et al. [26] characterized the critical volume of a bubble rising in a viscoelastic fluid using an FEM-based method and the exponential Phan–Thien and Tanner model; using a coupled LS-VOF ("VOSET") method, Wang et al. [27] studied drag reduction in cavity flow; Xie et al. [28] focused on droplet oscillation under a Maxwell model using lattice Boltzmann techniques. In contrast to constitutive modeling, the "micro-macro" approach [29] tackles the polymer-flow interaction using stochastic and Brownian Dynamics (BD) simulations [30–33] to retrieve the polymer stress tensor from the internal configurations of the polymer particles advected by the flow. Taking the CONNFFESSITapproach of Laso and Öttinger [34], Cormenzana and co-workers [35] and later Grande et al. [36] successfully handled free surface flows of polymer solutions, while Prieto [7,37] conducted multiphase simulations in viscoelastic fluids using a variance-reduced, stochastic implementation of a "micro-macro" method [38]. Further study of multiphase non-Newtonian flows was carried out by Bajaj et al. [39] and Xu et al. [40] using the Brownian Configuration Field (BCF) method of Hulsen et al. [41].

At present, there is a growing interest in Machine Learning (ML) [42,43] in the context of polymer simulation: Doblies et al. [44] employed ML as a means of predicting mechanical properties, while Jackson and collaborators [45] focused on the optoelectronic properties of conjugated polymers. It was also used by Kopal and co-workers in the prediction of the viscoelastic behavior of elastomer systems [46] using Radial Basis Functions (RBFs) or as a data-driven classification method to determine polymer/solvent compatibility by Chandrasekaran et al. [47]. Fluid dynamics of multiphase flow also benefits from this recent focus on ML: Ma and collaborators used statistical learning in [48] for bubbly systems; Ladický et al. accelerated multiphase simulations in GPUs using a data-driven approach with regression forests [49]; and Gibou and co-workers employed deep learning techniques with sharp interface methods in [50]. Hence, it seems unquestionable that ML and data-driven simulations are already having a tremendous impact within the scientific community, and the future possibilities seem nearly endless.

The main purpose of this paper is to highlight the effects caused by the non-Newtonian behavior of the polymer solution in a multiphase flow system, performing a series of numerical simulations by means of a computationally efficient, accurate, and robust numerical method based on a finite element discretization of the governing equations that uses ML-inspired techniques for the reconstruction of the polymer stress tensor, a feature that proves to be of the greatest importance for the accurate characterization of the viscoelastic flow. Thus, after presenting this Introduction, we describe the governing equations along with the aspects of the computational implementation in the Materials and Methods Section 2. Then, we move to Section 3, where we present results for drop deformation under steady, shear flows and in situations where gravitational effects drive the dynamics of the flow. Finally, Section 4 offers some conclusions and future lines of work.

### **2. Materials and Methods**

In this section, we describe the main ideas, mathematical background, and computational implementation of the FEM-based, ML-enhanced method used to perform the series of numerical experiments carried out in Section 3 to gain insight into the impact that viscoelasticity may have on drop deformation. We start with the finite element discretization, then moving on to the computational implementation.

### *2.1. Finite Element Discretization*

The problem of drop deformation in polymer solutions can be tackled using different methods. In this work, we use an FEM-based discretization of the "macro-scale" equations governing the fluid flow, employing a stochastic modeling of the stresses arising from the polymer fluid to account for the "micro"-scale. Finally, we use a Particle Level Set (PLS) method to capture the interface of the deforming drop.


**2. Diabetic ketoacidosis and cerebrovascular accidents**

Although cerebrovascular accidents represent a significant and well-known precipitating factor for DKA, the literature data on precise mechanisms, distinctive features or manage‐ ment guidelines for patients are quite few or missing. The prevalence of stroke as the precip‐ itating factor for DKA was 0% in some studies [40] to as much as 7% in others [24]. Considering the data from the recent study in USA, most of the DKA patients (e.g. 80%) were in the age 18-65 years, with only 18% younger than 18; even 24% of all patients with DKA were in the age 45-65 years [32] Based on these data, it seems that the prevalence of DKA in patients with stroke may be underestimated and its importance under-appreciated in many cases.

**DKA STROKE COMMENTS**

**Increased or decreased breathing frequency**, abnormal breathing patterns, Cheyne-Stokes type

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial

**Dry skin Skin may be dry**, or moisture A dehydration may occur in

sometimes low

High blood sugar level High sugar level in diabetics Due to the effect of counter-

Blood glucose levels are high in the majority of diabetic patients suffering stroke. Moreover, pH, bicarbonate and anion gap are not routinely monitored in all diabetic patients suffering stroke, at least not in secondary level health institutions worldwide. In conclusion, some of

Furthermore, there is striking lack of literature data concerning management of adult dia‐ betic patients with stroke. Although there are clear concerns about the volume overload, in‐ tensive use of osmotic and Henley's loop diuretics and the need for careful volume and monitoring in patients suffering cerebrovascular accident and DKA no clear guidelines were

uncommon

High ketone level in serum and urine Moderately high ketone level in urine

Low serum (<15 mmol/l) bicarbonate Serum bicarbonate usually normal

the DKA cases in patients with stroke may easily be overlooked.

produced for intensive care units and intensive care neurologic units.

**Table 2.** Symptoms and signs in diabetic ketoacidosis and stroke: the overlapping features

Low (<7.3) plasma pH Plasma pH usually normal

Increased ( >/12) anion gap Anion gap usually >/12

Different kinds of breath odor not

in diabetics, alcohol abuse, starvation

Breathing patterns may be similar and interchangeably assigned to either of the diseases stroke the clinical

Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 319

case of not having access to water or fluids, or intensive use

Fruity scented breath may be hardly recognizable. Moreover, the odor appearing after ingestion of various sweet and fruits may imitate the characteristic odor of DKA

regulatory hormones

of osmotic diuretics

examination

Abdominal pain Headache

**A generally ill appearance A generally ill appearance**

**Dry mouth, Often dry mouth Increased heart rate, Increased heart rate** Low blood pressure Mainly high blood pressure,

Shortness of breath,**increased rate of**

A distinctive fruity odor on the breath,

fruity-scented breath

**breathing** -Kusmaul's type

Cerebrovascular accidents lead to increased release of counter-regulatory hormones (cate‐ cholamines, cortisol) which lead to hyperglycemia. Hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glu‐ cose utilization by peripheral tissues. Also these hormones increase the release of free fatty acids from peripheral tissues and their utilization as the energy source in hepatic and mus‐ cle mitochondria (beta-oxidation) with the increased ketone production as the direct conse‐ quence. This sequence is identical to the one seen in acute myocardial infarction [32], [19].

There is a significant overlapping of the symptoms in stroke and DKA (table 2). One can as‐ sume that an interference of symptoms of the two conditions during the clinical examination may be confusing and their interpretation difficult particularly in elder and less communica‐ tive patients.

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 319

**2. Diabetic ketoacidosis and cerebrovascular accidents**

in many cases.

318 Type 1 Diabetes

tive patients.

Although cerebrovascular accidents represent a significant and well-known precipitating factor for DKA, the literature data on precise mechanisms, distinctive features or manage‐ ment guidelines for patients are quite few or missing. The prevalence of stroke as the precip‐ itating factor for DKA was 0% in some studies [40] to as much as 7% in others [24]. Considering the data from the recent study in USA, most of the DKA patients (e.g. 80%) were in the age 18-65 years, with only 18% younger than 18; even 24% of all patients with DKA were in the age 45-65 years [32] Based on these data, it seems that the prevalence of DKA in patients with stroke may be underestimated and its importance under-appreciated

Cerebrovascular accidents lead to increased release of counter-regulatory hormones (cate‐ cholamines, cortisol) which lead to hyperglycemia. Hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glu‐ cose utilization by peripheral tissues. Also these hormones increase the release of free fatty acids from peripheral tissues and their utilization as the energy source in hepatic and mus‐ cle mitochondria (beta-oxidation) with the increased ketone production as the direct conse‐ quence. This sequence is identical to the one seen in acute myocardial infarction [32], [19].

There is a significant overlapping of the symptoms in stroke and DKA (table 2). One can as‐ sume that an interference of symptoms of the two conditions during the clinical examination may be confusing and their interpretation difficult particularly in elder and less communica‐

**DKA STROKE COMMENTS**

**Frequent urination Incontinence** Frequent urination and

weakness in one arm / leg

**Loss of appetite Loss of appetite** Loss of appetite in DKA results

incontinence may be difficult to differentiate in a somnolent/

from predominantly catabolic pattern of metabolism, nausea

Mental status changes can be seen with mild-to-moderate DKA; more severe deterioration in mental status is typical with moderate-to-severe DKA.

comatose patient

and confusion

Excessive thirst or drinking lots of fluid Inability to swallow

**General weakness General weakness**, a feeling of

**Confusion, somnolence, stupor, comma Confusion, somnolence, stupor,**

**comma**

**Nausea and vomiting Nausea and vomiting**

**Table 2.** Symptoms and signs in diabetic ketoacidosis and stroke: the overlapping features

Blood glucose levels are high in the majority of diabetic patients suffering stroke. Moreover, pH, bicarbonate and anion gap are not routinely monitored in all diabetic patients suffering stroke, at least not in secondary level health institutions worldwide. In conclusion, some of the DKA cases in patients with stroke may easily be overlooked.

Furthermore, there is striking lack of literature data concerning management of adult dia‐ betic patients with stroke. Although there are clear concerns about the volume overload, in‐ tensive use of osmotic and Henley's loop diuretics and the need for careful volume and monitoring in patients suffering cerebrovascular accident and DKA no clear guidelines were produced for intensive care units and intensive care neurologic units.

Some of the management guidelines may be defined here:

**1.** It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration poten‐ tates a tendency toward intravascular thromboembolism. Since the use of osmotic and sometimes also other kinds of diuretics is inevitable in patients with stroke a careful hy‐ dration is recommended in order to avoid further thrombotic complications.

the cerebral metabolic state worsen. After initiation of DKA therapy, abnormalities in Pro‐ tein C, Protein S, plasma homo-cysteine, and von Willebrand Factor (vWF) were demon‐ strated [11, 9]. While protein C levels normalize with treatment, free protein S, the active

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial

Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 321

Arterial ischemic stroke [47], cerebral venous thrombosis [29], and hemorrhagic stroke [36] were noted in children following DKA. DKA-associated cerebral edema may also predis‐ pose to ischemic injury and hemorrhage, though cases of stroke without concomitant cere‐ bral edema have been identified [49]. As stroke itself may cause cerebral edema, it becomes difficult to ascertain whether cerebral edema in DKA is the cause or an effect of acute cere‐ bral infarction. A sub-arachnoid or intra-ventricular hemorrhage may occur without cere‐ bral edema as was demonstrated using on CT scanning. Clinically, a transcranial Doppler ultrasound in children with DKA demonstrated significant vascular dysregulation with vas‐ odilation, decreased cerebral blood flow velocity, and loss of normal cerebral blood flow regulation that only normalized after treatment. Another group of researchers found normal to increased cerebral blood flow with impaired cerebral auto-regulation during episodes of

Treatment with bumetanide, [27] an inhibitor of Na-K-2Cl Co-transport, resulted in im‐ provements in metabolic measures during untreated DKA and amelioration of the declines

It is clear that at least some of these mechanisms may be operative in adult DKA. Abnormal‐ ities in coagulation during DKA or its treatment have been also noted in adults. Indeed, an endothelial injury, platelet activation, relative hypo-fibrinolysis, and activation of the coagu‐ lation system [20] even in the absence of clinical signs of thrombosis were all demonstrated in patients with DKA. However, the up-regulation was not to a degree expected for the in‐ crease in coagulation activity (thrombin-antithrombin III complex and prothrombin frag‐

In summary, cerebrovascular accidents represent a significant and well-known precipitating factor for DKA. It seems that the prevalence of DKA in patients with stroke may be underes‐

It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration potentates a ten‐ dency toward intravascular thromboembolism. Unfortunately, like in acute myocardial in‐ farction, the volume replenishment capacity in patients with stroke is often limited. Intravenous insulin and monitoring and correction of possible electrolyte imbalances are the

Not only does stroke precipitate DKA, but the vice-versa is also true: diabetic ketoacidosis itself was reported to be a risk factor for the occurrence of stroke in children and youth. A cerebral hypo-perfusion occurs in untreated DKA and may lead to cerebral injury. Arterial ischemic stroke, cerebral venous thrombosis and hemorrhagic stroke were noted following

anticoagulant of protein S, is reduced and does not return to baseline with treatment.

DKA not associated with overt CE in 6 children [20].

in metabolic measures during initial DKA treatment.

timated and its importance under-appreciated in many cases.

ment 1 + 2 levels) at DKA presentation.

mainstay of the treatment.

DKA episodes.

Not only does stroke precipitate DKA, but the vice-versa is also true [20]: diabetic ketoacido‐ sis itself was reported as a risk factor for the occurrence of stroke in children and youth. The risk of acute ischemic or hemorrhagic stroke during the acute DKA episode is perhaps un‐ der-appreciated.

Systemic inflammation is present in DKA, with resultant vascular endothelial perturbation that may result in coagulopathy and increased hemorrhagic risk. Hyperglycemia and acido‐ sis may contribute to oxidative injury [25], as well as ischemic injury [34]. Thrombotic risk during DKA is also elevated by abnormalities in coagulation factors, platelet activation, blood volume and flow, and vascular reactivity.

Recent data demonstrate that DKA is associated with reduced cerebral blood flow and with brain cell swelling [23]. These data suggest that cerebral injury resulting from DKA may be similar to hypoxic/ischemic brain injury. A cerebral hypo-perfusion occurs in untreated DKA. [23] In analogy with ischemia/reperfusion injury, DKA could be associated with meta‐ bolic abnormalities similar to those of hypoxic/ischemic brain injury and that these abnor‐ malities would worsen during initial DKA treatment as normal cerebral perfusion is reestablished [15, 4].

Although a small percentage of children have clinically apparent cerebral injury at presenta‐ tion of DKA prior to treatment, neurological decline during DKA treatment is more com‐ mon [16]. During initial DKA treatment with insulin and intravenous saline, key aspects of the cerebral metabolic state worsen. After initiation of DKA therapy, abnormalities in Pro‐ tein C, Protein S, plasma homo-cysteine, and von Willebrand Factor (vWF) were demon‐ strated [11, 9]. While protein C levels normalize with treatment, free protein S, the active anticoagulant of protein S, is reduced and does not return to baseline with treatment.

Some of the management guidelines may be defined here:

use of diuretics may precipitate pro-thrombotic state.

may be a precipitating factor for stroke (see later)

sium levels or performing potassium substitution

blood volume and flow, and vascular reactivity.

der-appreciated.

320 Type 1 Diabetes

reestablished [15, 4].

**5.** Bicarbonate therapy is not recommended except in extreme acidosis.

**1.** It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration poten‐ tates a tendency toward intravascular thromboembolism. Since the use of osmotic and sometimes also other kinds of diuretics is inevitable in patients with stroke a careful hy‐

**2.** Fluid resuscitation must be performed carefully, in small aliquots, and with constant monitoring of blood pressure, hematocrit and plasma sodium; novel minimal invasive procedures [39] should have advantages over central venous catheter since CVP itself was reported to be a risk factor for cerebrovascular thromboembolism [33]. Excessive

**3.** Infused insulin is the principle therapeutic tool for fighting DKA in patients with cere‐ brovascular accidents. Since fluid resuscitation must be restricted, DKA itself is expect‐ ed to have more prolonged clinical course. This may be of importance, since DKA itself

**4.** Serum potassium must be carefully monitored in all cardiovascular patients with DKA (see earlier). Hyper or hypokalemia should be promptly corrected; thus said, insulin-in‐ duced intracellular shift of potassium must be taken in account when evaluating potas‐

Not only does stroke precipitate DKA, but the vice-versa is also true [20]: diabetic ketoacido‐ sis itself was reported as a risk factor for the occurrence of stroke in children and youth. The risk of acute ischemic or hemorrhagic stroke during the acute DKA episode is perhaps un‐

Systemic inflammation is present in DKA, with resultant vascular endothelial perturbation that may result in coagulopathy and increased hemorrhagic risk. Hyperglycemia and acido‐ sis may contribute to oxidative injury [25], as well as ischemic injury [34]. Thrombotic risk during DKA is also elevated by abnormalities in coagulation factors, platelet activation,

Recent data demonstrate that DKA is associated with reduced cerebral blood flow and with brain cell swelling [23]. These data suggest that cerebral injury resulting from DKA may be similar to hypoxic/ischemic brain injury. A cerebral hypo-perfusion occurs in untreated DKA. [23] In analogy with ischemia/reperfusion injury, DKA could be associated with meta‐ bolic abnormalities similar to those of hypoxic/ischemic brain injury and that these abnor‐ malities would worsen during initial DKA treatment as normal cerebral perfusion is

Although a small percentage of children have clinically apparent cerebral injury at presenta‐ tion of DKA prior to treatment, neurological decline during DKA treatment is more com‐ mon [16]. During initial DKA treatment with insulin and intravenous saline, key aspects of

dration is recommended in order to avoid further thrombotic complications.

Arterial ischemic stroke [47], cerebral venous thrombosis [29], and hemorrhagic stroke [36] were noted in children following DKA. DKA-associated cerebral edema may also predis‐ pose to ischemic injury and hemorrhage, though cases of stroke without concomitant cere‐ bral edema have been identified [49]. As stroke itself may cause cerebral edema, it becomes difficult to ascertain whether cerebral edema in DKA is the cause or an effect of acute cere‐ bral infarction. A sub-arachnoid or intra-ventricular hemorrhage may occur without cere‐ bral edema as was demonstrated using on CT scanning. Clinically, a transcranial Doppler ultrasound in children with DKA demonstrated significant vascular dysregulation with vas‐ odilation, decreased cerebral blood flow velocity, and loss of normal cerebral blood flow regulation that only normalized after treatment. Another group of researchers found normal to increased cerebral blood flow with impaired cerebral auto-regulation during episodes of DKA not associated with overt CE in 6 children [20].

Treatment with bumetanide, [27] an inhibitor of Na-K-2Cl Co-transport, resulted in im‐ provements in metabolic measures during untreated DKA and amelioration of the declines in metabolic measures during initial DKA treatment.

It is clear that at least some of these mechanisms may be operative in adult DKA. Abnormal‐ ities in coagulation during DKA or its treatment have been also noted in adults. Indeed, an endothelial injury, platelet activation, relative hypo-fibrinolysis, and activation of the coagu‐ lation system [20] even in the absence of clinical signs of thrombosis were all demonstrated in patients with DKA. However, the up-regulation was not to a degree expected for the in‐ crease in coagulation activity (thrombin-antithrombin III complex and prothrombin frag‐ ment 1 + 2 levels) at DKA presentation.

In summary, cerebrovascular accidents represent a significant and well-known precipitating factor for DKA. It seems that the prevalence of DKA in patients with stroke may be underes‐ timated and its importance under-appreciated in many cases.

It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration potentates a ten‐ dency toward intravascular thromboembolism. Unfortunately, like in acute myocardial in‐ farction, the volume replenishment capacity in patients with stroke is often limited. Intravenous insulin and monitoring and correction of possible electrolyte imbalances are the mainstay of the treatment.

Not only does stroke precipitate DKA, but the vice-versa is also true: diabetic ketoacidosis itself was reported to be a risk factor for the occurrence of stroke in children and youth. A cerebral hypo-perfusion occurs in untreated DKA and may lead to cerebral injury. Arterial ischemic stroke, cerebral venous thrombosis and hemorrhagic stroke were noted following DKA episodes.

Treatment with bumetanide, an inhibitor of Na-K-2Cl co-transport, resulted in improve‐ ments in metabolic measures during untreated DKA and prevented cerebral metabolic ag‐ gravation during initial DKA treatment.

However, even the severe symptoms may be hardly recognizable for they can mimic those of the underlying disease – e.g. DKA itself. Hipophosphatemia may be the cause of rhabdo‐ myolysis, which (though not often) can lead to occurrence of cardiomyopathy and acute re‐

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial

Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 323

Even after initiation of phosphate replacement, serum phosphate levels are often difficult to normalize, and a severe metabolic acidosis can last despite insulin-induced normalization of

In cases of severe acidosis, phosphate replacement is of paramount importance [31]. Howev‐ er, after initial-phase phosphate replacement, the re-institution of acid-base balance phos‐ phate re-shifts from intra- to extracellular space; this can lead to the hyperphosphataemia later in the course of treatment [13]. Therefore, serum phosphate levels should be monitored continuously. With the occurrence of acute renal failure, indications for haemodialysis in‐ clude oliguria, persistent metabolic acidosis resistant to standard therapy, fluid overload and hypertension. Early initiation of haemodialysis is not only effective against the direct consequences of acute renal failure - uremia and hypervolemia – but also contribute to rapid correction of metabolic acidosis and hypophosphatemia [28]. Indeed, the existing hypophos‐ phataemia is easily corrected once a normal acid-base balance is established by haemodialy‐ sis. Prompt institution of dialysis is important as the diabetic patient may tolerate uraemia less well. Uncontrolled ketosis may worsen hyperkaliemia and metabolic acidosis. Insulin requirements may be increased due to insulin resistance, or decreased due to impaired

The vast majority of patients require intermittent haemodialysis. Patients with cardiac dys‐ function or autonomic neuropathy tend to develop hypotension during treatment. Also, an‐ ticoagulation with heparin may increase the risk of hemorrhage from proliferative retinopathy, therefore prostacyclin may be a safer alternative [52]. Peritoneal dialysis may be complicated by peritonitis and chest infections. Also, haemodialysis allows greater fluid

Despite the strong prevalence of compromised immune status, constant state of protein mal‐ nutrition, frequent vascular accessing with a predisposition to significant infections, in‐ creased incidence of cardiovascular diseases, the occurrence of DKA in patients with chronic renal failure is quite rare. [41, 3]. Kidneys play a major role in insulin breakdown [38]; ad‐ vanced chronic renal failure is associated with both insulin resistance and decreased insulin degradation. The latter may lead to a marked decrease in insulin requirement. Therefore, many patients see an improvement in glycemic control when they progress to haemodialy‐ sis. Furthermore, in hyperglycemic dialysis-dependent patients volume contraction due to osmotic diuresis is not encountered. Since glycosuria and osmotic diuresis account for most of the fluid and electrolyte losses seen in DKA, anuric patients may be somewhat protected from dehydration. However they may still be prone to development of hyperkalemia and metabolic acidosis [37]. In persistent and long-lasting DKA, a substantial volume loss can

removal and remove restrictions for administration of drugs and nutrition [56].

nal failure.

blood glucose.

clearance of circulating insulin [38, 56].

**3.2. Diabetic ketoacidosis and chronic renal failure**


*4.1. Savings*

The importance of the concept of savings in financial education derives from the economy, from both macroeconomic and microeconomic approaches. From the macroeconomic view, savings is the surplus of income over what is spent on consumption [52]. Likewise, good financial intermediation between savers and investors increases the economic development of a nation [53]. In this sense, [54] indicated that, if a nation has high savings rates, this is correlated with economic growth, pointing out that there is a cycle between savings and prosperity. Hence, macroeconomic principles have led several authors to explore diverse concepts that contribute to improving the development of a nation. From a microeconomic view, an individual demonstrates a saving behavior if he/she balances current consumption against expected consumption. This indicates that a well-informed individual will not consume all his/her income and will save for difficult times [55]. Likewise, some approaches have indicated that an environment of uncertainty is relevant to having such savings in the future [56]. Moreover, other studies have incorporated liquidity restrictions derived from imperfections in credit markets [57]. Additionally, savings behavior is driven

by externalities produced by inadequate financial intermediation and by imperfections in the credit and insurance markets [58].


Influence of Maternal Exercise on Maternal and Offspring Metabolic Outcomes

*Filip Jevtovic and Linda May*

## **Abstract**

Epigenetic transmission of metabolic disease to an offspring increases their risk for development of metabolic disease later in life. With the increasing rates of obesity in women of child-bearing age it is critical to develop strategies to prevent perpetuating metabolic disease across generations. Maternal exercise during gestation imprints offspring metabolic phenotype, thus increasing their imperviousness to metabolic assaults later in life. In rodent models, maternal exercise before and during gestation leads to enhanced offspring glycemic control, mitochondrial bioenergetics, and lower adiposity, which decreases their risk for development of future metabolic disease. In humans, maternal gestational exercise decreases pregnancy complications and improves maternal and offspring metabolism on both the whole-body and the cellular level. Maternal exercise restores the obesity-induced metabolic derangements, restoring maternal and offspring metabolic phenotype. While unknown, different exercise modalities might have a differential effect, however, evidence remains scarce.

**Keywords:** pregnancy, prenatal, exercise, fetal, metabolism

#### **1. Introduction**

Rates of pediatric obesity are escalating worldwide. Increasing rates of childhood obesity are likely to translate into a high cumulative incidence of metabolic disease (i.e., type 2 diabetes mellitus (T2D)) and further exacerbate the strain on the healthcare system, public health, and global economy [1]. The development of obesity is often attributed to a combination of genetic and acquired environmental factors. It is well established that the epigenetic transmission of metabolic diseases to offspring will increase their risk for the development of metabolic disorders later in life [2]. Accordingly, environmental exposures (i.e., overnutrition) experienced by parents during intrauterine and early postnatal life will have profound effects on offspring health. Because of the increasing rates of obesity among individuals of child-bearing age, it is critical to develop strategies to prevent the transgenerational propagation of metabolic disease.

It is widely understood that physical activity induces an array of positive metabolic changes that can delay and/or reverse the deleterious effects of obesity. While the mechanisms of action behind the benefits of regular physical exercise are welldocumented, research has mostly focused on the person performing the exercise. Consequently, there is limited understanding in the mechanisms by which regular maternal exercise influences the metabolic phenotype of offspring. Further, while studies regarding the effects of maternal exercise on pregnancy, maternal, and offspring outcomes are available and reviewed [3–8], data which characterizes the mediating factors affecting offspring developmental programming is limited [9]. This is partly due to limitations in revealing the cellular and molecular mechanisms behind maternal exercise-derived benefits that stem from the inability to obtain neonate tissue samples (i.e., skeletal muscle (SkM)).

An understanding of the explicit alterations that maternal exercise causes in the offspring phenotype would allow for the characterization of novel targets and could be used to render different therapeutics for metabolic diseases. Further, elucidating the specific biological mechanisms induced by different exercise modalities could permit this lifestyle intervention to serve analogous to a targeted therapy. Thus, there is potential for different exercise modalities to be used in a prescription-like manner to generate a unique set of metabolic adaptations suitable for treating and/or reducing offspring predispositions to metabolic disease. In view of this possibility, the focus of this chapter will be on describing the mechanisms behind the effects of the maternal exercise on offspring metabolic programing. Emphasis will be on the analysis of the biological mechanisms behind specific metabolic adaptations that promote imperviousness to metabolic challenges (i.e., overnutrition) leading to obesity and T2D. Further, considering that mitochondrial dysfunction and insulin resistance (IR) are major constituents of these metabolic diseases, a focus will be on the alterations in offspring mitochondrial bioenergetics and glycemic control.

## **2. Learning from rodent models**

#### **2.1 Maternal obesity and offspring health**

The use of rodent models has allowed researchers to study how various environmental factors during critical windows of prenatal and early postnatal development alter metabolic phenotype and elicit tissue specific adaptations in progeny. Considering the ever-increasing rates of obesity, dietary habits, particularly overnutrition, during gestation have a critical role in fetal development and are often the focus of investigations. Maternal obesity and often concomitant IR increase the propensity of the development and transmission of metabolic disease onto progeny. A maternal obesogenic diet during fetal life readily programs first and second generation offspring into a T2D-like phenotype, even without additional dietary insults (i.e., overnutrition) administered to these generations [10].

Maternal obesity elicits multifaceted effects on offspring behavioral habits and physiology. Offspring from obese mothers have a tendency to be physically inactive and hyperphagic [11, 12]. Further, offspring adopt a metabolic syndrome-like phenotype with impaired glucose tolerance, higher blood triglycerides, cholesterol, and leptin, but lower adiponectin levels, which increases offspring predisposition for the development of cardiometabolic disease later in life [11, 12]. Maternal obesogenic diet consumption during gestation increases offspring adiposity primarily through adipocyte hypertrophy [12–14]. Adipocyte hypertrophy, rather than

#### *Influence of Maternal Exercise on Maternal and Offspring Metabolic Outcomes DOI: http://dx.doi.org/10.5772/intechopen.106566*

hyperplasia, is associated with lower insulin responsiveness, inflammation, and an overall dysregulation of systemic energy metabolism [15]. Increased adiposity is further accompanied by a greater intramuscular fat accretion associated with higher PPARγ mRNA expression which could contribute to the development of lipotoxicity-induced SkM IR observed in these offspring [13]. Offspring from obese mothers have a restricted SkM growth potential which subsequently decreases their SkM cross-sectional area [13]. These alterations combined with lower GLUT4 and insulin receptor mRNA expression, as observed in SkM of offspring from obese mothers, attenuates their potential for insulin-stimulated glucose uptake and increase the propensity of offspring to develop hyperglycemia [13]. Considering that SkM is responsible for the majority of postprandial glucose uptake, these alterations have a profound effect on glucose homeostasis and could increase the risk for the development of T2D. Finally, maternal overnutrition leads to the downregulation of pathways associated with mitochondrial oxidation and lowers mitochondrial electron transport protein expression, leading to mitochondrial dysfunction [14].

Together, these alterations can lead to derangements in energy metabolism later in offspring life and increase their proclivity for metabolic disease. In view of this, it is essential to explore the effects of different lifestyle interventions that can alleviate the detrimental effects of maternal obesity on offspring metabolic dysregulation. Regular exercise is known to be protective against metabolic derangements observed in obesity and T2D in mother and offspring. Accordingly, illumination of the effects of maternal exercise on offspring body composition, glycemic control, and mitochondrial functioning will underline mechanistic alterations behind enhanced metabolic phenotype.

### **2.2 Maternal exercise enhances offspring metabolic phenotype**

#### *2.2.1 Body composition*

While most studies support the notion that exercise before and during gestation has an effect on offspring body weight (BW), findings are inconsistent [9]. Reports remain divided between maternal exercise causing a decrease [16–20], increase [21, 22], or having no effect on litter [23–25] or pup BW [26–30]. Additionally, these studies remain divided between maternal exercise leading to less weight gain with aging in offspring or having no effect on age-related weight gain. For example, Quiclet and associates found no effect of maternal exercise on male offspring BW at weaning or at 7 months of age; however, in their subsequent study, a decrease in BW was observed at weaning and 3 months of age, despite using the same animal and exercise model [17, 28]. Similarly, despite the use of the same animal species and exercising method across studies, change in BW is inconsistent in male offspring from exercising mothers at ~12 months of age [29, 30]. In addition to BW, discrepancies regarding the effect of maternal exercise on body composition have been observed across studies and offspring gender [16–18, 21, 23–25, 27–29, 31]. Carter et al. [26] reported an increase in lean mass and subsequent decrease in fat mass in males ~12 months of age; however, this was not observed in female offspring. Conversely, lower body fat percentages in female offspring have been shown in other studies [16, 19, 31]. Nonetheless, it is worth noting that body composition changes seem to be more prominent in male offspring. This is potentially because of a tendency for

greater weight gain with aging; however, the exact reason for the sex-specific differences remains unknown [9].

With consideration of these inconsistencies, it is difficult to determine if offspring BW is a causal factor or is determined by alterations in the metabolic phenotype of the offspring. Interestingly, it has been observed that the alterations in BW, lean and fat mass are secondary to other metabolic improvements and often develop later in offspring life. For instance, improvements in glucose metabolism have been observed in multiple studies regardless of inconsistencies in BW and body composition changes between studies [16, 26, 29, 31]. This suggests that metabolic reprograming is, at least in part, independent of body composition changes and is more likely causal of these alterations with aging or subsequent metabolic challenges (i.e., overnutrition). Accordingly, significantly smaller BW and fat mass gains were observed in sedentary pups from exercised mothers who were fed a high-fat-high-sugar diet (HFHS) compared to HFHS-diet fed pups from non-exercising mothers [17, 20]. This suggests that subsequent nutritional manipulations in offspring may be needed to elicit changes in BW and body composition and to better understand the relationship between changes in BW and metabolic reprogramming.

#### *2.2.2 Glucose tolerance*

Since SkM and liver metabolic alterations have a profound impact on the development of systemic metabolic disease, it is important to address how maternal exercise alters metabolism of these tissues. Exercise prior to and during pregnancy increases glucose tolerance and insulin sensitivity across offspring lifespan independent of changes in BW [16, 17, 19, 26, 27, 30, 31] and persist in second generation progeny [32]. Interestingly, in offspring from metabolically healthy exercising mothers, improvements in glucose tolerance are mostly observed in adulthood of the animal rather than early stages of life (i.e., at weaning) [16, 18, 25, 26]. This might be the case considering that the effects of maternal exercise are "diluted" in offspring from metabolically healthy mothers, and therefore these effects might be more pronounced in offspring from mothers with obesity, considering the previously described metabolic derangements that maternal obesity elicits. Accordingly, offspring and maternal glucose intolerance stemming from maternal obesity can be rescued by maternal pregestational and gestation exercise, and this effect is evident in early offspring life [18, 25, 29–31, 33]. These findings suggest that maternal exercise could enhance the ability of offspring to resist the future development of IR; however, these improvements may not be readily observed in healthy offspring before adulthood or without a subsequent metabolic challenge.

Multiple *in vivo* and *in vitro* techniques have been used in studies to confirm that enhanced glucose disposal stems from improved offspring peripheral (i.e., SkM) insulin sensitivity as a result of maternal exercise. Improved insulin sensitivity in offspring from obese mothers seems to be driven by an increase in SkM GLUT4 expression [16, 18, 23, 26, 27]; however, improved glucose tolerance independent of the changes in GLUT4 expression has similarly been observed [29, 31]. This indicates that an improvement in glucose transport capacity is not the only mechanism responsible for improved glucose clearance. Offspring from exercising compared to sedentary mothers exhibit improved SkM insulin signaling cascade activation with insulin stimulation; this is evidenced by higher phosphorylation of Protein Kinase B, also known as AKT, a key mediator of insulin-stimulated glucose uptake [17]. In addition

#### *Influence of Maternal Exercise on Maternal and Offspring Metabolic Outcomes DOI: http://dx.doi.org/10.5772/intechopen.106566*

to the effects of maternal exercise on SkM, it is important to recognize that these adaptations extend to offspring liver, a major organ for regulating glucose disposal and production. Maternal exercise improves mature offspring hepatic insulin sensitivity and lowers hepatic glucose production during hyperinsulinemic-euglycemic clamp [16]. Similar effects have been observed in an *in vitro* model where isolated hepatocytes of offspring from exercising mothers exhibit enhanced glucose control across basal and insulin- and glucagon-stimulated states [31]. Greater glucagonmediated hepatocyte glucose production and insulin-mediated inhibition of glucose production suggest that maternal exercise improves liver glucose metabolism across different physiologic states (fasted vs. fed) [31]. Interestingly, it is worth noting that this effect is observed in offspring from exercising mothers independent of maternal metabolic status (healthy or obese). This suggests that while metabolic enhancements may be present, they may not be evident with measurements at the whole-organism level considering the multifaceted input of several organs [31]. In rodent models, it is clear, that maternal exercise negates the effects of maternal obesity through enhancements in offspring glucose metabolism, which lowers the potential for glycemic dysregulation in subsequent generations.

#### *2.2.3 Mitochondrial remodeling*

Maternal exercise lowers SkM and liver triglyceride content in offspring from both healthy and obese mothers [24, 29, 31]. Lower SkM and liver triglyceride content will decrease the chance of lipid accumulation-induced impairments with insulin signaling and are suggestive of an enhanced oxidative capacity. Maternal exercise increases offspring SkM mitochondrial density, length, and mitochondrial DNA content [19, 34]. These mitochondrial alterations predominantly stem from the effects of maternal exercise on PGC-1α, a key mediator of mitochondrial functioning and biogenesis [19, 34]. Maternal exercise before and during pregnancy attenuates high-fat diet (HFD) induced PGC-1α promoter hypermethylation in offspring SkM, and is able to rescue a HFD induced decrease in PGC-1α gene expression [19, 27]. Interestingly, the effect of maternal exercise on PGC-1α expression has only been observed in adult offspring [27]. This, however, may be an artifact of the rapid proliferation and differentiation of SkM cells during early growth compared to mature SkM, when myogenic cells are quiescent and transcription of genes is predominantly influenced by gene methylation [27]. Higher PGC-1α expression in SkM increases expression of its downstream targets including cytochrome C, a central component of the electron transport chain, which potentiates improvements in the regulation of oxidative phosphorylation [27]. Additionally, in SkM of offspring from exercising mothers, greater cytochrome C oxidase and citrate synthase activities have been observed [34], suggesting that maternal exercise has an effect on mitochondrial oxidative capacity. It is worth noting that similar hypermethylation and lower mRNA expression of PGC-1α is seen in SkM of individuals with T2D [35]. This points to maternal exercise as a potential therapy to ameliorate the transgenerational transmission of mitochondrial dysfunction in humans, by increasing the oxidative capacity as well.

In liver, the maternal exercise induced increase in PGC-1α mRNA expression is accompanied by higher protein expression of phosphorylated AMP-activated protein kinase (AMPK), which is considered to be a master regulator of energy metabolism [36]. This AMPK-PGC-1α axis and its increase is paralleled by an increase in PPARα mRNA expression and is suggestive of a greater potential for fatty acid oxidation.

Specifically, maternal exercise enhances gene expression of Acox1 and Acacb, enzymes involved in fatty acid handling and oxidation [36]. Interestingly, while improving the capacity for fatty acid oxidation, maternal exercise simultaneously decreases the potential for fatty acid storage by lowering PPARγ mRNA expression, a gene associated with hepatic steatosis [36, 37]. Further, greater phosphorylated AMPK expression in offspring from exercising mothers leads to greater phosphorylation of acetyl-CoA carboxylase which lowers the availability of malonyl-CoA, a precursor for fatty acid synthesis [36]. It is important to note that these adaptations on a cellular level extend to elicit whole-body protection and lead to lower BW gain and hepatic steatosis after pups are challenged with an obesogenic diet [36]. Overall, maternal exercise driven improvements of offspring mitochondrial bioenergetics are often seen as vital for proper metabolic functioning and resilience to metabolic challenges in adult life. These adaptations could influence the predisposition for the development of metabolic disease by altering mitochondrial substrate "preference" and oxidation capacity.

Maternal exercise increases the affinity for pyruvate and palmitoyl-CoA in offspring SkM mitochondria suggesting easier access of these substrates for the oxidative phosphorylation system (OXPHOS) [17]. Further, maternal exercise has no effect on the Km for palmitoyl-carnitine, which suggests that maternal exercise might be acting specifically on CPT-1, a commonly altered enzyme in obesity-related diseases. Finally, a larger decrease in enzyme affinity is seen for palmitoyl-CoA compared to pyruvate suggesting that maternal exercise increases offspring SkM preference for fatty acid oxidation and potentially explains the previously described decrease in triglyceride content [17, 29]. In addition to altering SkM metabolic pathways, offspring from exercising mothers exhibit greater levels of liver mRNA expression of genes involved in pyruvate metabolism (Pklr, Pcx), the tricarboxylic acid cycle (Pdha1, Pdk4, CS, Idh3a, Mdh2), and fatty acid transport and oxidation (Cd36, Fatp4, Acox, Cpt1) [31]. Together, this data shows that maternal exercise induces an array of adaptations that enhance substrate handling and subsequently increase resilience against future metabolic disease.

Data regarding maternal exercise and offspring OXPHOS capacity is limited. Maternal exercise decreases complex II and III activity and increases complex IV activity [22]. Additionally, when ADP-stimulated respiration is measured in SkM mitochondria from offspring of exercising mothers, there seems to be no effect on complex I and complex I + II respiration; however, data regarding respiration through complex II only is inconsistent with maternal exercise resulting in a decrease or having no effect on complex II maximal respiration [22, 23]. Interestingly, in isolated liver mitochondria from offspring of exercising mothers, lower complex II and higher complex IV activity and content is observed, and accompanied by lower maximal respiration through complex I, II, and I + II. Interestingly, respiratory control ratio (RCR) is lower in offspring mitochondria from both liver and SkM when respiration is supported through complex I and complex I + II [22]. As an index of how coupled respiration is to ADP phosphorylation, this would suggest a lower capacity for phosphorylating respiration to offset electron leak; however, implications about the effect of maternal exercise on offspring mitochondrial efficiency cannot be made as RCR, when used as a proxy of mitochondrial coupling, does not always match the ATP/O ratio, which is a direct measure of mitochondrial coupling [38]. Data regarding alterations in offspring energy efficiency come from oxygen consumption rates in free living conditions. Accordingly, on the level of the whole organism, maternal exercise increases the basal oxygen consumption rate, subsequently protecting offspring

from overnutrition-induced obesity by increasing their energy expenditure [20, 30] Together, the limited data suggests that maternal exercise results in adaptations in mitochondrial respiration, but no conclusive remarks can be made considering the inconsistencies between and limited number of studies.

#### *2.2.4 Mitochondrial redox balance*

While mitochondria are often described predominantly in the light of energy metabolism, it is important to recognize their function in maintaining redox homeostasis. Mitochondria are mediators of redox balance, and this is influenced by alterations to pro- and antioxidant systems. Disruption of the redox balance due to alterations in mitochondrial bioenergetics or the redox buffering capacity are considered to be an integral part in the etiology of metabolic disease (i.e., IR) [39]. Maternal exercise lowers hydrogen peroxide production with complex II only and complex I + II supporting substrates in both SkM and liver mitochondria [22]; however, the effects seen in SkM are inconsistent across studies indicating maternal exercise may not affect hydrogen peroxide emission [23]. Interestingly, SkM and liver mitochondria from offspring of exercising mothers are protected from reverse electron transport linked hydrogen peroxide emission [22]. Hydrogen peroxide emission via reverse electron flow is often associated with overnutrition and suggests that maternal exercise has a protective effect on offspring redox balance during future metabolic challenges such as overnutrition [39]. In addition to lower hydrogen peroxide emission and subsequently lower reactive oxygen species (ROS) production, maternal exercise enhances glutathione activity in blood and liver [22]. Further, offspring from exercising mothers have lower blood thiol content suggestive of a higher antioxidant capacity. These adaptations are paralleled with higher offspring liver alpha-tocopherol which increases free radical scavenging ability and decreases lipid peroxidation [40–42]. Maternal exercise further induces a mitochondrial fatty acid profile shift by increasing short-chain and decreasing long-chain fatty acid content [22]. These changes can be beneficial considering that short-chain fatty acids are more resistant to free radical attack and peroxidation and have a positive influence on redox signaling [43, 44]. Finally, maternal exercises increases offspring LON protease (an oxidative stress induced mitochondrial degradation catalyst) and TFAM induced autophagy; these changes are suggestive of a greater mitochondrial turnover rate and overall lower susceptibility to oxidative stress induced mitochondrial dysfunction [24, 34]. Together, these findings suggest that maternal exercise increases antioxidant capacity, decreases ROS production, and lowers the potential accumulation of less functional mitochondria in offspring.

Together, maternal exercise will protect offspring from maternal obesity induced metabolic derangements and has the capacity to increase offspring resilience against future metabolic challenges. Further, offspring metabolic adaptations (**Figure 1**) as a result of maternal exercise seem to be independent of body composition alterations. These adaptations include improvements in offspring glucose and fatty acid metabolism across two major metabolically active tissues, the liver and SkM. In part, these adaptations are linked to mitochondrial structure remodeling, enhanced bioenergetic function, and greater redox capacity. Finally, it is imperative to keep in mind that cellular metabolic programing precedes improvements detected at the whole-body level making *in vitro* assessments indispensable for the understanding of maternal exercise-induced fetal programing.

**Figure 1.**

*Maternal exercise enhances offspring metabolism across two major metabolically active tissues, the liver and SkM. Offspring from exercising mothers have lower body weight (BW) and body fat (BF%) gain with age and exhibit enhanced whole body glucose tolerance. Additionally, maternal exercise leads to greater insulin sensitivity, mitochondrial remodeling, and improved bioenergetic function and substrate metabolism in peripheral tissue. Abbreviations: BW, body weight; BF%, body fat percentage; and OXPHOS, oxidative phosphorylation.*