Surgical Management for Meckel’s Diverticulum: A Case Series and Literature Review - Juniper Publishers

Journal of Surgery - Juniper Publishers

Abstract

Introduction: Meckel’s diverticulum (MD) is the most common developmental anomaly of the gastrointestinal tract [1]. MD is typically asymptomatic, however it can cause complications such as bleeding in children and small bowel obstruction in adults [2].

Cases: Two adult patients presented to Tullamore Hospital with features of small bowel obstruction (ileus). Both patients underwent CT scan, subsequent diagnostic laparoscopy and diverticulectomy of inflamed MD. The third case is a 12yr old boy who was presented to Khartoum Teaching Hospital with PR bleeding, then after two days developed abdominal distension and tenderness, with significant drop on hemoglobin. The patient underwent exploratory laparotomy which demonstrated MD with two perforated peptic ulcers at the ileum. Wedge resection was performed for the MD and primary repair of the ulcers after biopsy and edge refashioning. The post-operative period passed uneventfully for all three patients, with outpatient clinic follow up.

Discussion: The appropriate operation for symptomatic MD can be aided using a recommended HDR as cutoff 2.0 [3]. Basal ligation and frozen biopsy offer a novel and effective operative technique, as it can significantly shorten operative time [4]. For hemorrhagic ulcers and perforation, segmental and wedge resection for MD is recommended [5].

Conclusion:The laparoscopic approach was found to be effective as a diagnostic and therapeutic modality in patients with symptomatic MD. The foremost therapeutic objective is to achieve complete resection of MD along with ectopic mucosa. The HDR aids in determining whether diverticulectomy or wedge resection is the most appropriate MD resection technique

Keywords: Meckel’s diverticulum; CT-Abdomen & Pelvis; Height-Diameter Ratio; Heterotopic Gastric Mucosa; Per-rectum; Chest X-Ray

Abbreviations: MD: Meckel’s diverticulum; CT-AP: CT-Abdomen & Pelvis; HDR; Height-Diameter Ratio; HGM: Heterotopic Gastric Mucosa; PR: Per-rectum; CXR: Chest X-Ray.

Introduction

Meckel’s diverticulum is the most common developmental anomaly of the gastrointestinal tract with a prevalence of 2.0%. MD is reported to be up to four times more frequent in men [6]. This anomaly is understood to result from incomplete obliteration of the omphalomesenteric duct [1]. MD is a true diverticulum found at the antimesenteric border of the ileum, two feet proximal from ileocecal valve, two heterotopic mucosae found on MD, and two inch in length (The role of two) [5]. Usually MD is an asymptomatic, incidental finding however it can often cause complications such as small bowel obstruction due to inflamed Meckel’s or forming a loops of small bowel may become entangled around a fibrous cord. Meckel’s diverticulum can also lead to intussusception, volvulus, adhesions, stricture, and ileus or may become incarcerated within a hernia sac as in the litter hernia [2]. The aim of surgical management is to respect the diverticulum and all associated ectopic mucosa [7].

Case Presentation (1)

A 65-year-old male presenting to Tullamore Regional Hospital, complaining of abdominal pain, vomiting and absolute constipation for 3 days prior to admission. The patient’s abdomen was distended with generalised tenderness, however no surgical scars were observed. The patient’s admitted and laboratory results were as follows: Hb 13.0 units/dL, WCC 12.13 units/dL, CRP 15.5 units/dL, K+ 3.9 units/dL. A working diagnosis of small bowel obstruction was made, and the patient received I.V. fluids with nil per mouth. A CT-AP Figure 1 was ordered which confirmed a small bowel obstruction and the patient was consented for an emergency diagnostic laparoscopy.

Radiological Findings (Case 1) (Figure 1)

Procedure (Case 1)

Intra-operative laparoscopic exploration revealed an inflamed MD, and the entire small bowel was dilated sparing only last 60cm of distal ileum. Complete diverticulectomy was performed for inflamed MD with a linear stapler Figure 2. Subsequent histopathological analysis reported only an inflamed MD with no ectopic mucosa or neoplasia. The post-operative period passed uneventfully. The patient was discharged home in good condition on day four post-op. He was reviewed in the Outpatient’s Clinic six weeks later. The patient reported no post-operative complaints and the wounds well-healed.

Intra operative images (Case 1): (Figure 2).

Case Presentation (2)

A 12-year-old boy was admitted to the Paediatric Surgical Unit in Khartoum Teaching Hospital with abdominal pain and bleeding per rectum. On examination the patient’s abdomen was soft, with right sided tenderness. Digital rectal exam was normal with no haemorrhoids or anal fissure noted. Two days postadmission the patient developed generalized abdominal pain, vomiting and there was abdominal distension and peritonitis. Routine haematological investigations revealed the patient’s serum haemoglobin had dropped from 14grams to 11grams. The patient therefore received a 50ml/kg transfusion of packed red blood cells, as well as IV antibiotics and I.V. fluids. An erect chest x-ray Figure 3 showed air under diaphragm. In discussion with the patient’s family, the consent was made for a laparotomy.

Radiological Imaging (Case 2): (Figure 3)

Procedure (Case 2): A right lower transverse laparotomy incision was made to explore the bowel. Surgical exploration revealed a short Meckle’s Diverticulum with a wide base at the distal ileum with two perforated peptic ulcers. The MD was removed via wedge resection. The perforated ulcer edges were then biopsied and refashioned before closure via primary repair. Postoperatively, intravenous antibiotics and PPI infusion were given, and postoperative period passed uneventfully, the patient tolerated oral intake. The patient was discharged on day seven post-op with follow up in the outpatient clinic in three months. Histology afterwards confirmed a completely resected MD with ectopic gastric mucosa.

Case Presentation (3)

A 60-year-old male presented to the emergency department of Tullamore Regional Hospital with signs and symptoms of small bowel obstruction beginning 2 days prior to admission. Examination revealed a distended abdomen with generalised tenderness. Routine investigations: WCC 8.23 units/dL, CRP 31.9 units/dL, K⁺ 4.2 units/dL. The patient was admitted for nasogastric tube suction, I.V. fluids and analgesia. A CT-AP showed partial small bowel ileus with dilated loops of small bowel Figure 4. The patient was consented for an emergency diagnostic laparoscopy.

Radiological Imaging (Case 3): (Figure 4)

Procedure (Case 3)

Laparoscopic exploration detected an inflamed MD at the distal ileum with cord adhesion to the umbilicus Figure 5. Dilated small bowel was observed proximal to the adhesions. The inflamed MD was resected at the base with a linear stapler (diverticulectomy). The histopathology report showed an inflamed MD with ectopic gastric mucosa. The post-operative period passed unremarkably. The patient was discharged day three post-op and reviewed at OPD at 4 weeks with well healed wounds and no post-operative complaints.

Intra operative images (Case 3)

(Figure 5)

Discussion

Symptomatic Meckel’s diverticulum typically occurs in the first two decades of life and almost exclusively before the fifth decade [6]. The adult cases outlined above both contradict this pattern given both patients were above 60 years of age. In adults, MD is usually an asymptomatic condition with only about 4% of those affected developing complications [8]. The reported mechanism of intestinal obstruction in MD includes intussusception, adhesion, and volvulus. Furthermore, inflammation of the MD can cause small bowel ileus as seen in our two adult cases [1]. While obstruction is the most common complication in adult patients, gastrointestinal bleeding is the most common presenting symptom of MD in children [2]. This aligns well with the presenting complaints of the three cases in this report. Moreover, another study reported haemorrhage as the most common presentation in children and is reported in over 50% of their symptomatic cases [7]. Other complications of MD include perforation, umbilical fistula, cyst, fibrous cord with umbilicus, while double Meckel’s and carcinoid tumour are also reported in the literature [8]. 90% of bleeding diverticula contain heterotrophic mucosa, most often gastric mucosa (71%), contains acid-secreting parietal cells which can lead to ulceration and haemorrhage as observed in our paediatric case. Histopathological analysis demonstrates ectopic pancreatic tissue in 12.0% of resected MD [6].

The diagnosis of MD may be challenging as the condition often remains asymptomatic or may mimic various diseases which obscures the clinical picture. For example, MD often mimics the presentation of acute appendicitis in children, as 11% of complicated MD were initially misdiagnosed as acute appendicitis [8]. The probability of onset of complications decreases with age, therefore the diagnosis of MD in adults is often incidental [9]. Exploratory laparoscopy is an important diagnostic tool, especially when perforation has occurred [9]. In the case of hemorrhage, as often seen in pediatric MD, mesenteric angiography and embolization are reported as diagnostic and therapeutic tools [5, 10]. The advent of technetium (Tc) 99m radionuclide scanning has greatly facilitated the diagnosis of MD especially when the anomaly contains heterotopic mucosa [5]. Since Meckel’s diverticulum (MD) is rarely diagnosed in adults, there is no consensus on the optimum operative technique for asymptomatic MD. Indeed, there is disagreement as to whether an incidentally discovered MD should indeed be respected at all [11]. However, research suggests up to 57% of resected MD were found incidentally which contradicts the view that routine resection is not indicated in incidentally discovered cases [3].

Resection of incidental MD is explicitly not recommended in patients with peritonitis, major abdominal trauma, ascites, or in the context of older age, malignancy, or immunosuppression. However, research does suggest resection of incidental MD may be appropriate in the context of risk factors which may predict future complications. Risk factors for MD complications include male gender, age younger than 40 years, diverticulum longer than two centimeters, narrow neck of the diverticulum and the presence of macroscopically mucosal abnormalities noted at surgery [11]. On the other hand, some researchers disagree with the view that the external appearance of the MD can reliably predict the presence of HGM, and therefore argue macroscopic appearance cannot reliably aid resection decisions in the context of an incidentally discovered MD [3]. Nevertheless, the definitive treatment of symptomatic MD is laparoscopic or open diverticulectomy via wedge or segmental resection. The type of procedure depends on; (a) the integrity of diverticulum base; (b) the presence and location of ectopic tissue within MD [8]. Location of ectopic mucosa can be predicted based on height-to-diameter ratio. Long diverticula (height-todiameter ratio >2) have ectopic tissue located at the body and tip, whereas short diverticula have wide distribution of ectopic tissue surrounding the diverticulum base. A greater HDR has also been found to be an independent risk factor for perforation [11].

When indication of surgery is simple diverticulitis, diverticulectomy should be performed for long and wedge resection for short MD [11]. Simple transverse resection is not recommended for short MD, as resection followed by anastomosis seems preferable to wedge resection or tangential mechanical stapling, in order reduce the risk of leaving behind abnormal heterotopic mucosa [4]. New operative methods for MD include basal ligation combined with intraoperative frozen section. Using intraoperative histological feedback on the existence of residual ectopic mucosa, surgery is either terminated or further wedge intestinal resection or bowel resection was performed as required. Basal ligation is a safe and effective operation method as it can significantly shorten operation times and postoperative fasting time. For hemorrhagic ulcer and perforation, segmental and wedge resection are indicated as performed in our pediatric case [5,12-15].

Conclusion

The laparoscopic approach was found to be effective as a diagnostic and therapeutic modality in patients with symptomatic MD. Once MD has been diagnosed, the fundamental therapeutic aim is to achieve complete resection of the diverticulum along with ectopic epithelium. The HDR can assist in determining the most appropriate resection technique. Longer MD should be resected with diverticulectomy whereas wedge resection is the optimum technique for short MD.

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Violence Against the Older Adults: A Brazilian Tragedy - Juniper Publishers

 Forensic Sciences & Criminal Investigation - Juniper Publishers

Abstract

Context and Objective: The occurrence of suspected cases of abuse against older adults is a global phenomenon; health professionals must pay close attention to the possibility of abuse against this population. This study aimed to describe the profile of notifications of abuse against older adults reported in SINAN (the official database of the Brazilian Ministry of Health) between 2009 and July 2014.

Design: Cross-sectional study.

Setting: The manuscript was produced in the Department of Legal Medicine of the Medical School of Universidade de São Paulo and ABC Faculty of Medicine.

Methods: Data on domestic, sexual, and other forms of violence were obtained from the Ministry of Health’s official website (Sistema de Informação e Agravos de Notification – SINAN) between 2009 and July 2014 (http://dtr2004.saude.gov.br/ sinanweb/index.php). The selected subjects were elderly aged 60 years or older of both sexes.

Results: The number of notifications showed a proportional increase between 2009 and mid-July 2014; most of the attacks occurred in the victims’ homes, and the most frequent aggressors were sons or daughters, followed by unknown people and acquaintances. Women were the most attacked. Many aggressions were recurrent and in multiple forms, but physical aggression and negligence were the most reported.

Conclusion: This study’s great importance is exposing the quantitative data of this violent scenario so that health professionals who care for older adults remain alert to the possibilities of mistreatment and that they notify suspected or proven cases, as determined by Brazilian law.

Keywords: Older adults; Abuse; Neglect; Physical signs; Incidence; Violence

Introduction

With the global growth of the elderly population, specific issues related to this group of individuals should be widely discussed. Among these issues is violence, which is essential because mistreatment of older people is associated with distress and increased mortality [1]. Therefore, it is a serious public health problem.

Abuse is defined as violating an individual’s human and civil rights. The abuse might consist of a single or repeated act, often affecting vulnerable people and occurring in any relationship. The following six types of abuse have been described: physical, sexual, psychological, financial, or material, neglect or act of omission, and discriminatory [2]. According to the Brazilian Institute of Geography and Statistics (IBGE) [3], in 1950, older adults comprised 4% of the country’s total population; in 1991, they represented 7.3%; 8.6% in 2000 (14.5 million) [4]; and 10% in 2010. Thus, according to the World Health Organization (WHO), Brazil is experiencing a rapid increase in the number and percentage of older people, often within a single generation, and needs to adjust to this new reality [5]. Brazilian laws are strict regarding the notification of confirmed or suspected cases of abuse against older people. Law nº. 12.461 (2011), amended Article 19 of the Statute of the Elderly (Law nº. 10.741/2003), is more rigorous than the previous law. It mandates that the notification of abuse against older adults be compulsory, even in suspected cases, and should be performed by health authorities through private and public health services and any official agency (Police authority; Public Ministry; Municipal Council for the Elderly, the State Council of the Elderly, and the National Council for the Elderly) [5,6].

Concerning the sub notification, Cooper et al. [1] in a systematic review published in 2008, concluded that 6% of older people reported significant abuse in the last month, 5.6% of couples reported physical violence in their relationship in the last year, and one in four vulnerable elders are at risk of abuse; however, only a tiny proportion of this abuse is currently detected. In Brazil, according to the Information System of Aggravation of Notification (SINAN Net), which is associated with the Brazilian Ministry of Health, there were significant fluctuations in the total numbers of specific notifications of abuse and violence-related deaths among people over age 60 between 2009 and 2011 [7]. In 2009, there were 1748 notifications of abuse, 2.5% of which resulted in death; 3298 notifications of abuse, with 1.17% of these resulting in death, occurred in 2010, and 5307 notifications of abuse, with 4.6% of these cases resulting in death, occurred in 2011 [6,7]. Mascarenhas et al. [7] evaluated many aspects of the reports of violence against older adults in the Brazilian Health Services [7,8]. These authors described the victims’ profile as Caucasian males, between 60 and 69 years of age, single or widowed, with low education levels, and with no physical disabilities or mental or behavioral disorders. Physical violence was prevalent among men, whereas psychological violence, sexual violence, and neglect were more prevalent among older women [7,8]. Another Brazilian study showed that women over 75 years of age, single or widowed, with low education levels and chronic diseases, are primary abuse victims [8,9]. This data will facilitate the assessment of the primary at-risk groups suffering from violence and provide information for establishing public policies to reduce the number of abused elderly individuals. Thus, medical physicians and forensic examiners should recognize these signs to identify cases of abuse against older adults and avoid recurrences in non-fatal violence and vengeful perpetrators.

Objectives

This study aimed to describe the profile of notifications of abuse against older adults reported in SINAN (the official database of the Health Ministry of Brazil) from 2009 to July 2014.

Methods

The results of this cross-sectional study were conducted through analysis of data published on the official website of the Brazilian Ministry of Health: SINAN Net. (http://dtr2004.saude. gov.br/sinanweb/). The information in this database included notifications of violence (domestic, sexual, and other types of violence against the older adults), which were included in the list of compulsory notifications of violence according to the Ordinance GM/MS Nº 104, January 25, 2011. We analyzed the notifications from 2009 to July 2014. The study parameters included the sex and age of the victim, the victim’s relationship to the perpetrator, the place of the aggression, and the type and form of the aggression. The results were compared with data from the literature.

Results

Total numbers

In the period from January 2009 to July 2014, the SINAN (official database of the Brazilian Ministry of Health) received 655,720 compulsory notifications of violence, and 35,155 of these cases involved the older adults population (over 60 years of age), representing 5.36% of the total.

Setting of the aggression, sex, and ethnicity of the victims

68% of these cases (24,167) occurred in the victim’s residence, and were reported 12,314 cases recurrent violence, which resulted in 1111 deaths. The women were the most frequent victims, accounting for 54% of total aggressions (maintaining the ratio above 50% for all study years), ethnicity was Caucasian (Graph 1), and 33,3% had low levels of education.

In the analyzed period, the average percentage of elderly victims of total violence remained stable, at around 5.14%, compared to the total violent notifications (all ages), as shown in Table 1.

The physical violence and deaths

However, from 2009 to July 2014, notification of physical violence against older people increases in Brazil (Graph 2). The partial number of notifications until July exceeded the total number in 2011. In 2010 there was an increase of 103% compared to the previous year; in 2011, the increase compared to 2010 was 58,7%, and 68,44% in 2011 compared to 2012. However, there was a slowdown in 2013 when the increase in notification was 14,69% concerning 2012. The total of notifications of physical abuse was 23,542 in the period (2009 to July 2014), with 1111 deaths (Graph 3); 14,000 cases were caused by beating.

Physical abuse was more frequent in men (51,5%) than women, but the difference was irrelevant. The perpetrators were sons or daughters in 4,305 notifications. A stranger was the aggressor in 3,304 cases; friends were 2,696, and husband or ex-husband, the number of notifications, was 2,478. In the 2,558 aggressions, the instrument used was the knife.

Neglect, abandonment, and sexual violence

Neglect and abandonment were the second most frequent kind of violence against older people. In the period of this study, 9,296 notifications were performed, with 129 deaths. Women were the preferred victims, 4,872 cases (52,4%). Table 2 shows the notifications according to race. There were 9,241 cases of sexual and psychomoral violence reported during the period, of which 6,595 were women (71.36%). Considering only reports of isolated sexual violence, there were 782 cases, 94.91% of which involved women.

Discussion

Our study showed that 5.36% of the total notifications from January 2009 to July 2014 were related to older people.

A Portuguese study applied between January and June 2013 demonstrated that 23.5% of older adults have suffered some abuse, emotional and neglect especially; these results were obtained through a questionnaire [10], which may have facilitated the complaint. In Brazil, in 2013, notifications of violence against the older population were 5.7%. According to the WHO, 36% of American nursing home staff reported witnessing abuse in the past year, with 10% witnessing physical abuse and 40% witnessing psychological abuse.^9,10 These data do not show the true scope of this type of crime, as most abusers are close relatives (i.e., sons and daughters). Another study (a systematic review of the prevalence of abused elderly individuals) showed that the prevalence of abused elderly individuals varies according to culture and the definition and measure of violence. According to these authors, 25% of older adults are at risk of abuse, although few cases have been identified1. Many forms of violence are imposed against older people, as these victims are vulnerable individuals who are often unable to react to attacks or depend on the abuser. In some situations, an old individual has difficulty understanding the violent act or does not want to report the abuser due to their relationship. The term “abuse against the elderly” has often been associated with physical aggression; however, neglect and emotional abuse (psychological) play essential roles [9,11]. Few studies consider neglect as a separate form of abuse. The definition of abuse against the elderly is complex, involves multiples phenomena, and varies considerably among researchers and between the laws of different countries, even among the states of a country, as in the U.S. Concerning determining the age limit of elderly individuals, some studies suggest ages above 60 years. In contrast, others only consider ages over 65 years. This varying definition is a problem that affects epidemiological studies of the incidence of these events. According to Akaza et al. (2010), other confounding factors involve the different classifications of the types of maltreatment (violence). For some authors, violence is classified into four types (physical, emotional, financial, and neglect). In contrast, others add self-neglect, sexual abuse, and other miscellaneous forms of abuse [11,12]. The prevalence of elderly abuse is difficult to determine, as some studies define older adults as over 60. In contrast, other studies consider people over 65 years. Although all people can be battered, the most frequent victims are vulnerable individuals, such as children, teenagers, women, homosexuals, people with disabilities or mental disorders, and the elderly [8,11]. The Ministry of Health warns that falling accidents among the elderly and their consequences have become an epidemic in Brazil, with more than 20,000 hospitalizations in 2009. The Brazilian government recommends that all physicians who evaluate elderly individuals suffering from falls (accidental or not) ask these individuals whether there were any other injuries or falls in the last six months [12,13].

In 2007, according to the Ministry of Health, 18,946 older adults died from external causes, representing the seventh leading cause of death, and 125,000 hospitalizations were recorded that same year. In 2010, the WHO reported that 41 elderly individuals die each day worldwide from external causes, representing this group’s sixth leading cause of death, emphasizing that these events remain incredibly underreported [13,14]. In our study, relatives, mainly daughters, and sons, were the significant perpetrators of abuse against older people, and the aggression occurred inside the home. These data were similar to those observed in medical literature. Alcoholism among the offenders was a factor in many reports. Other similarities between the Brazilian results and the descriptions in the literature showed that women were the principal victims. The differences between the gender data obtained in SINAN were mild, although women were the most victimized every year [7,14]. These results were similar to those of Souza et al. [15], perhaps reflecting the greater longevity of women [15].

Although abuse against the elderly is not recent, only from the late 1980s, it has become a topic of interest. Indeed, the notifications recorded in the databases do not represent the actual number of deaths or injuries suffered within this population. Under notification might partially reflect that the clinical manifestations of abuse are often mistaken for the manifestations of diseases inherent to aging [15,16] (e.g, bruises). Some studies show that the presence of bruises greater than five centimeters in size on the lateral arm or right shoulder, neck, head, thoracolumbar region, buttocks, and soles of the feet are not often observed in accidental injuries and should be considered to result from an act of violence [17].

Multiple wounds in different stages of cicatrization; bruises at different stages of evolution (purple, brown, green, yellow, and finally brownish yellow); injuries in the shape of any instrument, marks of containment on the wrists, ankles, and heels; traumatic alopecia, edema of the scalp, and fractured teeth or nose or burns are other warning signs. Radiological images showed that misaligned fractures in different stages of consolidation could also be signs of physical aggression [17-21]. On the other hand, pressure sores, localized areas of tissue damage, or necrosis are common in the older population. However, Santos et al. [20] state simple care can prevent pressure sores. Therefore, the presence of these lesions might be an indicator of inadequate care. Is important to point out that, as Mosqueda et al. [22] say, “innocent bruises frequently occur on the extremities”. Although recognizing this abuse is difficult due to physiological aging, it should always be considered, particularly when the clinical history contradicts the findings of physical or laboratory examinations.

Another explanation for the low rate of notification of abuse against the elderly is that health professionals are not attentive to this possibility and that older people frequently are silent victims. The violence perpetrated through negligence principally occurs in a domestic environment and frequently involves the family, which makes diagnosis difficult. In many instances, the victim does not report the violence because they do not understand the incident as a form of violence or are afraid to report their close relatives as the perpetrators. According to Minayo [13], deaths, injuries, and trauma from traffic accidents and falls could also suggest negligent acts committed by the authorities or people involved with the accessibility of the elderly individual. Finally, we have to remember that signs suggestive of sexual violence injuries are also frequent, and include itching, anal or vaginal bleeding and pain, sexually transmitted diseases, and spotting or bleeding in the underwear21. Physicians, including coroners, should pay attention to elderly individuals with these lesions during their examinations, as there are many types of abuse against the elderly, and the diagnosis is difficult.

Final Considerations

The importance of our study is to show the large number of cases of violence that occur in our country, totaling 23,542 cases in the period studied, with an unspeakable tragedy represented by the 1,111 deaths that occurred in this period. Notably, our study also showed that assistance from health professionals facilitates the identification and confirmation of cases of maltreatment against the elderly and reporting, which is required by Brazilian law. Worrisome, this study showed that the number of abuse notifications against the elderly has grown in Brazil. Men and women are victims of physical, sexual, and neglect abuse, often recurrent and fatal. With the increasing life expectancy of the world population, issues involving older individuals are becoming common in medical practice. Among these issues, violence against older adults must be analyzed carefully, as many forms of violence leave no visible marks (neglect, psychological and economic violence), and many injuries to the elderly result from advanced age (fractures from falls and bruises). The information provided to physicians does not always represent the truth. Thus, physicians need to be alert to the possibility of violence against older adults, as the recurrence of maltreatment, and to report suspected or confirmed cases.

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Endophytic Microbial Remediation of Heavy Metals: An Overview - Juniper Publishers

 Biotechnology & Microbiology - Juniper Publishers

Abstract

Technological explorations (chemical fertilizers, pesticides, timber preservatives, polythene, microelectronic, synthetic textiles, mining extractions, smelting, aerosols, metallurgic extractions, leaching, automobile exhausts, sewage sludge, coal combustion products, pharmaceutical and hospital wastes) are the major source of heavy metal contamination and pollution in the environment). Metal contaminated sites have been effectively cleaned by a process called bioremediation. This bioremediation process has emerged as an effective application to remediate heavy metal pollution. Heavy metal remediation by plants is known as phytoremediation which is time consuming process. Further, high concentrations of pollutants lead to toxicity of the remediating plants. This situation could be overcome by exploring the plant intriguing microbes, which would improve the plant growth by facilitating the appropriation of toxic heavy metals. Through in-situ rhizospheric process, plants can bioconcentrate phytoextraction and bioimmobilize phytostabilization of toxic heavy metals. The properties such as bioavailability and mobility of heavy metal are very critical factors in the rhizosphere where root uptake of heavy metals takes place. These factors affect the rate of phytoextraction and phytostabilization. The uptake of heavy metals can be enhanced significantly by its solubilization in soil through reaction with ligands, which allow the formation of mobile complexes. Endophytic fungi take part in this mechanism of enhancing heavy metal solubilization by producing organic compounds like citric acid and oxalic acid, which form complexes and enhance heavy metal reclamation processes.

Keywords: Heavy Metals; Endophytes; phytoremediation; Antimicrobial activity; Secondary metabolites; Soil pollution

Introduction

Heavy metals causing soil pollution has become one of the most severe worldwide environmental problems. For the last two decades, industrial explorations/activities have been leading to a continuous enhancement in heavy metal (chromium, nickel, lead, mercury and cadmium) discharge into the soil, rivers and ocean. Different sources of heavy metals include Hospital waste, e-waste, batteries, lamps, thermal plants, chlor-alkali plants, pesticide industry, paints, mining, coal industries, thermal industries, sulphuric acid plants, mining, smelting, pyrolysis and pharmaceutical industries [1]. Table 1 clearly denotes the different sources of each and every heavy metal. Continuous increase of metal levels in soil and water poses a health risk to humans and animals through the food chain and or contaminated drinking water. The dispersion of heavy metals through different sources including mining, pesticides, pharmaceutical, crude oil and metal emission was clearly represented in Figure 1, [2].

Different conventional methods such as reverse osmosis, evaporation, adsorption, precipitation, ion exchange and electro chemical methods have been used for the removal as well as treatment of heavy metal contaminating sites [3,4]. However, conventional methods involve application of more reagents, high energy, high cost and result in incomplete and ineffective removal as well as producing toxic metal sludge [2]. Bioremediation has emerged as a potential tool to treat heavy metal contaminated sites [5]. Different microbes are capable of reducing the heavy metal stress on plants, enhance the bioavailability of metal for plant uptake and promote growth [6]. Fungal endophytes live inside the healthy plant tissues and show significant metal-binding capacity [7] and provide more advantages over bacterial endophytes [8].

Heavy Metal Pollution

In our everyday life a wide variety of hazardous materials are released into natural resources from different kinds of industries including chemical, biochemical, pharmaceutical, fertilizer, pesticides, battery industries [9]. Among different pollutants, heavy metals are of major concern to human health due to their cytotoxicity, carcinogenicity, and mutagenicity [10]. Phytoremediation, the use of plants to remediate polluted soils, an eco-friendly and cost- effective approach receiving considerable global attention for a decade [11]. A large number of plant species are capable of hyper accumulation of heavy metals in their tissues; however, phytoremediation in practice has several constraints at the level of sites as these are with a variety of different contaminants [12]. Further, the success of phytoremediation of metals depends upon a plant’s ability to accumulate high concentrations of the metals [13]. Heavy metalhost plant- endophyte associations have been the objective of particular attention due to the potential of microbes for bioaccumulation of metals from polluted environment or its effects on metal mobilization/immobilization and consequently enhancing metal uptake and plant growth. The present review explains how the mutual partnerships between plants and their associated endophytes can be exploited as a strategy to accelerate plant biomass production and influence plant metal accumulation through different mechanisms including adaptive strategies, metal mobilization, and immobilization mechanisms.

Endophytic Microbes

Endophytic microbes are intriguing microorganisms present inside the plant tissue with mutual/symbiotic relationship. Endophytes provide plant’s protection by triggering signaling pathway through the elicitation of signal molecules/ phytohormones/secondary metabolites. Endophytes stimulate plant growth by biosynthesizing plant proteins and other molecules. Endophytes are involved in biotransformation and biocatalytic processes. Endophytes enhance the nutrient solubilization and nutrient uptake by plants. Endophytes stimulate in vitro seed germination, and enhancement of production of plant secondary metabolites. Endophytes act as bio controlling agents, biofertilizers and biopesticides. Further endophytes are involved in pollution control, and heavy metal remediation (bioremediation/phytoremediation) through different mechanisms. Endophytic microbes in different ways affect plant growth. Endophytic microbes can actively or passively promote growth through a variety of mechanisms. and there are a large number of soil microorganisms that do not appear to directly affect plant growth one way or the other, although this may vary as a result of a range of different rhizosphere soil conditions including organic matter, pH, temperature, nutrients, and pollutants level [14,15]. Endophytes accelerate phytoremediation of metalliferous soils though modulation of plant growth promoting parameters, by providing plants with nutrients, and by controlling disease through the production of antifungal metabolites.

Rhizobacteria

Rhizobacteria, an abundant symbiotic/mutualistic partner of plants, are considered plant growth promoting bacteria [16]. Among the soil microbes, the plant growth promoting bacteria (PGPB) deserves special attention. In general, PGPB migrates from the bulk soil to the rhizosphere of plant and colonize the rhizosphere and roots of plants [17]. The mechanisms behind plant growth stimulation differ between PGPB strains and certainly depend on the various metabolites released by these strains of PGPB. For example, production of different phytohormones such as cytokinins, auxins, gibberellins, and ethylene are mainly attributed to the presence of different strains of PGPB [18,19]. These hormones can alter plant growth together with bacterial secondary metabolites usually in a dose-dependent manner [20,21]. Other beneficial compounds produced by PGPB include organic acids, osmolytes, enzymes, antibiotics, siderophores, biosurfactants, and nitric oxide etc. All of these compounds are responsible for tolerance to abiotic stresses [22,23] associated nitrogen fixation [24] improved mineral uptake [25] suppression of pathogenic microorganisms [26,27] etc. Together, these are responsible for plant higher tolerance to heavy metal stress and stimulate host plant growth via different mechanisms including biological control, production of growth regulators, enhancement of mineral nutrients and water uptake, induction of systemic resistance in plants to pathogens, and nitrogen fixation [28]. Additional benefits due to bacterial endophytes are plant physiological changes including accumulation of osmolytes and osmotic adjustment, stomatal regulation, reduced membrane potentials, and changes in phospholipid content of cell membranes [29-35]. Table 2 denotes metal resistant features of PGPB to the plants.

Metal resistance mechanism of PGPB

Iron is a necessary cofactor for many biological reactions and hence is an essential nutrient for all organisms. In aerobic conditions, iron exists predominantly as ferric state (Fe3+) and insoluble hydroxides and oxyhydroxides which are unavailable to plants and microbes. Bacterial siderophores can bind Fe3+ and solubilize this metal for its efficient uptake. Some plants produce phytosiderophores which typically have a lower affinity for iron than bacterial siderophores. Further, heavy metals that are accumulated in plant tissues also cause changes in different vital plant growth processes and also possess negative effects on iron nutrition. Under such conditions, the siderophore producing rhizosphere bacteria is capable of chelating Fe3+ and making it available to plant roots. Then the roots are able to take up iron from siderophores-Fe complexes through different plausible mechanisms [36]. Various instances of increased Fe uptake in plants with co-stimulation of plant growth because of PGPB inoculations have also been reported [37]. Siderophores also promote bacterial IAA synthesis by reducing the detrimental effects of heavy metals through chelation reaction [38]. Phosphorus (P) is one of the major essential macronutrients for biological growth and development. Under stressed conditions, most metal-resistant PGPB can convert these insoluble phosphates into available forms through different mechanisms [39]. An increase in availability of phosphorous to plants through the inoculation of PSB (phosphate solubilizing bacteria) has been reported in pot experiments [40,41]. In addition, fixation of atmospheric N2 is a metabolic ability of endophytes and rhizobacteria and colonization offer different benefits to the host plant [42] including the production of enzymes, siderophores [43] and antibiotic metabolites [44] and induction of systemic resistance in plants [45,46]. Some metalresistant PGPB have been reported to produce enzymes such as chitinase, beta 1,3 glucanase, protease, and lipase, by which they can lysis the cells of fungal pathogens [46]. The interaction of plant–PGPB–phytopathogens in metal contaminated soils remains poorly understood due to both pathogenic and non-pathogenic microbes depend on the properties of surrounding environment (rhizosphere/tissue interior of plants) and hence these plantassociated microbes may modulate responses to direct and/or indirect effects of metal toxicity.

Metal mobilization in phytoextraction

Among the various metabolites produced by PGPB, the siderophores play a significant role in metal mobilization and accumulation [47,48]. Siderophores produced by PGPB solubilize unavailable forms of heavy metal-containing Fe and also form complexes with bivalent ions which can be assimilated by root mediated processes [49,50]. Braud et al 2009 [50] investigated the exudation of Cr and Pb in soil after inoculation of various PGPB. Pseudomonas aeruginosa was able to solubilize large amounts of Cr and Pb in soils. P. aeruginosa is used as only a model system since regulatory agencies will never give permission for the release of this bacterium to the environment. Inoculation of Zea mays with P. aeruginosa increased Cr and Pb uptake into the shoots. Bacterial culture filtrates containing hydroxamate siderophores secreted by Streptomyces tendae F4 significantly enhanced the uptake of Cd by the plant, compared to the control shows that siderophores can help to reduce metal toxicity in bacteria while simultaneously facilitating the uptake of such metals by plants [47]. PGPB has been shown to increase heavy metal mobilization by the secretion of organic acids such as gluconic acid, citrate, oxalate, malate, acetate, and succinate, etc. Production of 5-ketogluconic acid by endophytic diazotroph Gluconacetobacter diazotrophicus, which dissolves Zn sources such as ZnCO3, Zn3 (PO4)2, and ZnO thus making Zn available for plant uptake [51]. The biosurfactants produced by PGPB have also been demonstrated to enhance heavy metal mobilization in contaminated soils [52]. Sheng et al [53] reported that the inoculation of soils with biosurfactant producing Bacillus sp. J119 significantly enhanced Cd uptake in plant tissue and biomass of tomato plants. From the above findings, it can be concluded that inoculating the seeds/soils with selected bacteria, it is possible to improve bioavailable metal concentrations for plant uptake and thereby phytoextraction potential in metal-contaminated soils.

Metal immobilization in phytostabilization

Phytostabilization shows heavy metal tolerance and assists plant growth. Plant-associated bacteria have evolved several mechanisms by which they can immobilize/transform metals and make them inactive. The active mechanisms behind heavy metal resistance in bacteria includingmetal exclusion by active transport from the cell extra cellular sequestration of metals with polymers chemical modification and detoxification makes metal inactive [54]. Binding of metals to ionic functional groups such as sulfhydryl, sulfonate, hydoxyle, carboxyle, amide and amine groups immobilizes the metal and prevents entry into the plant root. Similarly, extracellular polymers such as polysaccharides, proteins, and humic substances detoxify heavy metals by chelation [55]. Organic acids and siderophores can reduce the metal bioavailability and toxicity by chelation mechanism [56,57]. According to Dimkpa et al. [57] the decreasing Ni concentration in cowpea plants is indicative of a Ni binding potential of hydroxamate siderophores. Madhaiyan et al. [58] reported that endophytic bacteria, such as Magnaporthe oryzae and Burkholderia sp. increased plant growth but reduced the Ni and Cd accumulation in roots and shoots of tomato and also their availability in soil. Bacteria can interact directly with the heavy metals to reduce their toxicity: metal dissolution by strong organic acids produced by bacteria (i.e., H2SO4 produced by Thiobacillus); production of organic bases resulting in metal hydroxide precipitates; fixation of Fe and Mn on the cell surface in the form of hydroxides; biotransformation via oxidation, reduction methylation, demethylation, volatilization, complex formation [59]. The role of soil microbiota, specifically rhizospheric and endophytic microbes, in the development of phytoremediation techniques has to be elucidated in order to speed up the process and to optimize the rate of accumulation/absorption/mobilization of heavy metal contaminants. The bioavailability ratio of metals to plant roots is considered a critical requirement for plant metal bioconcentration or bio immobilization to occur. In this view, it is possible to employ endophytes to alter the bioavailability of metals for improving phytoremediation of metal contaminants on a large scale.

Role of endophytes in metal remediation

Endophytes are intriguing microorganisms that reside inside the healthy plant tissue and show mutualistic relationship with plants. The symbiotic relationship between plants and endophytes was first reported in 1697. Endophytes play an important role in increasing crop yield by secretion of secondary metabolites which increase the rate of plant metabolism, in turn increasing the crop yield. Endophytes protect plants against many pathogens by secreting secondary metabolites. Endophytes induce multiple benefits to plants by colonizing plant roots [60,61]. By colonizing plant roots, endophytes become part of a symbiotic plant-microbe system.

For instance, the plant growth, metal accumulation/metal tolerance, endophyte colonization, and plant growth promoting potentials must be met for microbial assisted phytoremediation to become effective. Further the concentration of bioavailable metals i.e., bioavailability in the rhizosphere greatly affect the quantity of metal which will be accumulated in plants, because a large proportion of metals are bound to different inorganic and organic components in polluted soil and their availability is closely related to their speciation [62]. The metabolites released by PGPB (e.g., biosurfactants, siderophores, organic acids, and phyto regulators, etc.) can alter the uptake of heavy metals directly and indirectly: directly, through chelation, acidification, immobilization, precipitation, and oxidation–reduction reactions in the rhizosphere. Indirectly, through their effects on plant growth dynamics.

Many studies proved that endophytic mcrobes significantly contribute to their host plant towards many stresses such as high salinity, drought, extreme temperature, and heavy metal toxicity, and oxidative stress [63]. Endophytic microbes were proved to have potential for phytoremediation and might be utilized as biosorbents for the detoxification of heavy metals [64]. Moreover, recent studies have demonstrated that many endophytes are metal resistant, able to enhance plant growth and able to degrade organic contaminants. Endophytes could promote host plant growth in heavy metal contaminated soils. Heavy metal resistant endophytic microbes are capable of promoting host plant growth, biomass production and enhanced metal extraction. Furthermore, they alleviate the toxic effect of heavy metals by regulating various biochemical processes inside the plant through the production of different metabolites and phytohormones that help the host plant avoid metal stress toxicity [65]. It has been reported that 76 endophytic microbial isolates were isolated from sewage, sludge and industrial effluents.

Four identified microbes screened for their resistance to four heavy metals including cadmium (Cd), chromium (cr), nickel (Ni) and lead (Pb), Cadmium (Cd), Chromium (Cr) and Nickel (Ni) and Copper (Cu). These endophytic microbes were identified as fungal isolates including Aspergillus niger, A. terreus, Trichoderma viride, and T. longibrachiatum and they showed tolerance to Pb, Cd, Cr, and Ni [66]. In a study by Fazli et al. [67] it has been proved that Aspergillus versicolor and Trichoderma sp. showed tolerance index to Cd. Jenny et al. [68] ninety-three endophytic fungal isolates were identified from Nypa fruticans sp. Eight of them showed resistance to metals such as Pb, Cr, and Cu. These eight fungal isolates were closely related to Pestalotiopsis sp. and showed tolerance against metals such as Cr, Cu, Zn and Pb. Scleroderma citrinum isolated from mining sites, Pisolithus tinctorius strains Pt1 and Pt2 isolated from unpolluted sites. The biomass production of Scleroderma citrinum was increased in presence of Cd while Pt1 and Pt2 biomass was reduced in presence of Cd. The tolerance index of S. citrinum was higher when compared to Pt1 and Pt2. The mycelium of P. tinctorius strains Pt1 and Pt2 accumulated more Cd than S. citrinum mycelium [69]. Various species of Penicillium have been proved to show resistance against heavy metals such as manganese (Mn), aurumn (Au), thorium (Th), uranium (U), cadmium (Cd), nickel (Ni) and lead (Pb). Examples of Penicillium in heavy metal removal include P. italicum, P. oxalicum, and P. chrysogenum [70].

Among the Penicillium species, P. chrysogenum has been studied the most and P. chrysogenum was demonstrated to adsorb Cr(III), Ni, and Zn, as well as Pb, Cd, and Cu [70]. Five endophytes isolated from roots including P. mustea, P. chrysanthemicola, G. Cylindrosporus, E. Salmonis and C. cladosporioides. G.Cylindrosporus were resistant to Pb, Zn and Cu and exhibited strong growth when compared with other fungi [71]. niger has the ability to remove various heavy metals such as Pb, Cd, and Cr from aqueous solution [72]. A. niger showed potential affinity for binding with Cu, Zn and Ni ions in a single composition system, while it only showed binding properties for Cu and Zn in a multi-metal solution [73]. Auricularia polytricha exhibited tolerance to metals such as Pb, Cd, and Cu. FTIR (Fourier transform infrared) analysis indicated that functional groups such as carboxyl, phosphoryl, hydroxyl, amine/amino, and C–N–C were the main functional groups that affect the metal biosorption process. SEM observations showed that the surface of the raw biomass was smooth and uniform with regular and plain structure. The surface of Cd and Cu loaded biomass was changed when compared with control. The surface of Pb loaded biomass was much rougher. The metal ions as spot-like particles distributed on the surface of the Cd and Pb loaded fruiting body, while extra flake-like substances distributed on the surface of the Cu loaded biomass [74].

Fusarium solani was found to tolerate a number of heavy metals and other metals such as Cr, Pb, Hg, Ni, Li, Co, Al, Mn, As, Fe, Cu, Zn. Certain morphological changes such as bulbous hyphae, increase in number of spores, thickened cell wall, and changes in the shape and size of the cultures in presence of metals were observed during of the culture in response to metal. Pigment production also played a role in higher tolerance to metal [75]. Hongmei et al. [76] reported the 53 isolates of endophytic fungi from the roots of Salix variegata. Among them 27 isolates were selected to test their metal tolerance against Cd. Four isolates were further tested for minimum inhibitory concentrations (MICs) against Cd and observed that Paraphaeosphaeria sp. was the most tolerant endophyte with highest MIC value. Deng et al. [77] reported that a total number of 33 fungal isolates were isolated from stems of Portulaca oleracea. Among them, Lasiodiplodia sp was resistant to Cd, Pb and Zn. FTIR analysis revealed that biosorption process of endophytic fungi Lasiodiplodia sp. was due to the functional groups such as hydroxyl, carbonyl, amino, and benzene ring on the cell wall.

The inoculation of endophytic fungi increased the biomass of Brassica napus L, translocation factor of Cd and the extraction amount of Cd by rape in the Cd and Pb contaminated soils. The endophytic fungi P. funiculosum from soybean plant showed resistance to Cd and Cu. The heavy metal resistant P. funiculosum association with soybean plants significantly increased the shoot fresh biomass, shoot length, and root fresh biomass when compared with non-inoculated endophyte plants under Cu stress. Protein and chlorophyll content were significantly higher in endophyte inoculated plants as compared to non-inoculated endophyte plants under Cu stress condition. Cu tolerance rate was significantly higher in endophyte inoculated plants compared with non-inoculated endophyte plants. Anzhi Reni et al. 2011 [78] reported that endophyte infection of host Lolium arundinaceum significantly increased the biomass under Cd stress. Endophytic infection increased Cd accumulation in L. arundinaceum and Cd transport from root to shoot was significantly higher when compared with endophyte free plants. The endophyte-plant relationship was a resembling model for endophyte assisted phytoremediation of heavy metal contaminated soils. Neotyphodium infected two grass species Festuca arundinacea and F. pratensis under Cd stress showed increased shoot, root and total biomass than endophyte free plants. Cd accumulation was higher in shoot and root of endophyte infected plants (F. Pratensis and F. arundinacea) compared with non-infected plants. Cd accumulation was higher in roots compared to shoot. The endophyte infected plants had higher potential to remove Cd from contaminated soil than non-infected plants [79]. Olivier et al. [80] showed that Glomus intraradices fungi was inoculated to Medicago truncatula under Pb, Cd and Zn stress. The root and shoot biomass were increased compared to non-inoculated plants. Cd and Zn content in shoot was increased in G. intraradices fungi inoculated plants when compared with non-inoculated plants. Kanwal et al. [81] also reported that G. intraradices inoculated M. Sativa plants showed significant increase in chlorophyll content, plant growth and biomass under Cd and Zn toxicity compared to non-inoculated plants. Table 3 shows the different endophytes and their resistance to different heavy metals.

Endophytes Role in the Ecosystem

Endophytes play crucial roles in ecosystems by protecting plants against many biotic and abiotic stresses, increasing their resilience, and helping plants to adapt to new habitats [82-89]. Biotic stresses from which endophytes can provide protection include plant pathogens, insects and nematodes. Abiotic stresses include nutrient limitation, drought, salination, and extreme pH values and temperatures. In return, plants provide spatial structure, protection from desiccation, nutrients and, in the case of vertical transmission, dissemination to the next generation of hosts [90,91].

Concluding Remarks and Future Perspectives

Endophytic microbes exhibit remarkable phytoremediation property through various approaches including metal sequestration, metal immobilization, metal absorption and accumulation of heavy metals. Endophytic microbes produce proteins, polysaccharides, organic acids and other bioactive compounds to effectively phytoremediate metal- contaminated soils. Bioavailability of metals to plant roots is considered a critical requirement for bio-concentration/bio immobilization to occur. In this regard, it is suggested to employ beneficial endophytes to alter the bioavailability for improving phytoremediation on large scale.

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Weight Loss in Diabetes: Pharmacological Management and Other Strategies - Juniper Publishers

 Diabetes & Obesity - Juniper Publishers

Abstract

Diabetes and obesity are prevalent metabolic disorders that present a significant global public health challenge. This review article provides a comprehensive overview of pharmacological and surgical management strategies for weight loss in diabetes. Diabetes, characterized by high blood glucose levels, and obesity, resulting from excessive body fat accumulation, are closely linked, making effective management essential. Pharmacological interventions for weight loss in diabetes include metformin, which can lead to modest weight reduction in some patients. GLP-1 receptor agonists, such as Semaglutide, liraglutide, and exenatide, offer effective glycemic control and weight loss options. Dual GIP/GLP-1 agonists, particularly Tirzepatide, show promise in treating diabetes and obesity with significant weight loss and glycemic control observed in clinical trials. SGLT-2 inhibitors, like dapagliflozin and empagliflozin, not only manage diabetes but also offer cardiovascular benefits and weight reduction. Amylin mimetics, exemplified by pramlintide, regulate post-meal glucose levels, suppress glucagon secretion, and promote satiety, leading to sustained weight reduction in diabetic patients. Gastric bypass surgery, an option for select individuals with obesity and diabetes, shows significant weight loss and improved metabolic profiles. By understanding these treatment options, healthcare professionals can develop personalized management plans combining lifestyle modifications, pharmacotherapy, and surgery where appropriate. Such approaches can lead to better patient outcomes, including weight loss and improved metabolic control. Ongoing research is essential to explore the long-term efficacy and safety of these interventions to optimize diabetes and obesity management in diverse patient populations.

Keywords: Diabetes mellitus; Obesity, Weight loss; Pharmacological management; Surgical management; Metformin; GLP-1 receptor agonists; Semaglutide; Liraglutide; Exenatide; Dual GIP/GLP-1 agonists; Tirzepatide; SGLT-2 inhibitors; Dapagliflozin; Empagliflozin; Amylin mimetics; Pramlintide; Gastric bypass surgery

Abbreviation: DM2: Type 2 Diabetes Mellitus; GLP-1 RA: Glucagon-like Peptide 1 Receptor Agonist; FDA: U.S. Food and Drug Administration; CKD: Chronic Kidney Disease; SGLT2i: Sodium-Glucose Cotransporter 2 Inhibitors; T2DM: Type 2 Diabetes Mellitus; BMI: Body Mass Index; GLP-1: Glucagon-like Peptide 1; DPP-4: Dipeptidyl Peptidase-4; LRYGB: Laparoscopic Roux-en-Y Gastric Bypass; HDL - High-Density Lipoprotein

Introduction

Diabetes is a metabolic disorder characterized by high blood glucose levels due to inadequate insulin production or impaired insulin action. It can lead to severe complications affecting various organs and systems in the body, such as the heart, kidneys, nerves, and eyes. Obesity, in contrast, is a condition in which excessive body fat accumulates, leading to an increased risk of various health problems, including diabetes [1,2]. The risk factors for diabetes include genetics, sedentary lifestyle, unhealthy eating habits, obesity, and age. Type 2 diabetes mellitus (DM2), the most common form, is closely linked to obesity, as excess body fat can lead to insulin resistance and impair the body’s ability to regulate blood sugar levels [1-3]. The epidemiology of obesity and diabetes is concerning, with both conditions showing a significant increase worldwide. In the United States, approximately 34.2 million people have diabetes, representing about 10.5% of the population.

Obesity in the US is even higher, affecting around 42.4% of adults [3]. Diabetes and obesity rates also rise in other countries, contributing to a global public health challenge [4]. The pathogenesis of weight gain in diabetes is multifactorial. In type 2 diabetes, insulin resistance plays a key role, as the body’s cells do not respond adequately to insulin, leading to decreased glucose uptake and increased fat storage. Moreover, certain medications used to treat diabetes, such as insulin and sulfonylureas, can promote weight gain by stimulating fat storage and reducing appetite control [5]. Complications of obesity in diabetes can be severe and affect various organ systems. Cardiovascular complications include an increased risk of heart disease, stroke, and high blood pressure. Diabetes-related obesity can also lead to complications such as diabetic retinopathy, diabetic neuropathy, kidney disease, and non-alcoholic fatty liver disease [4-6]. Treating obesity in diabetes involves a combination of lifestyle modifications, pharmacotherapy, and sometimes bariatric surgery.

Lifestyle changes, including a healthy diet, regular physical activity, and behavior therapy, are the cornerstone of management. Pharmacological interventions may include medications that promote weight loss or reduce appetite, such as GLP-1 receptor agonists and SGLT-2 inhibitors [1-8]. This article aims to provide a comprehensive overview of pharmacological management and other strategies for weight loss in diabetes. By understanding the definition, risk factors, epidemiology, pathogenesis of weight gain, complications, and treatment options for obesity in diabetes, healthcare professionals can develop practical approaches to managing these interconnected conditions and improve patient outcomes.

Metformin

Metformin is an oral anti-diabetic medication commonly prescribed for managing DM2. Its mechanism of action involves reducing hepatic glucose production, enhancing peripheral insulin sensitivity, and increasing glucose uptake by skeletal muscle. Metformin does not stimulate insulin secretion from the pancreas [9-11]. The typical dose ranges from 500mg to 2,000 mg per day, divided into two or three doses [10,11]. It is usually taken with meals to minimize gastrointestinal side effects. The duration of treatment is generally long-term, as metformin is considered a foundational therapy for type 2 diabetes [9-13]. Metformin is indicated for patients with type 2 diabetes, particularly those who have not achieved glycemic control with diet and exercise alone. It can be used as monotherapy or in combination with other oral anti-diabetic medications or insulin. The drug is generally welltolerated, but common adverse effects include gastrointestinal disturbances such as nausea, diarrhea, and abdominal discomfort.

Metformin is contraindicated in patients with renal impairment, significant hepatic disease, or a history of lactic acidosis [11-13]. Regarding its efficacy for weight loss, metformin may lead to modest weight reduction in some individuals with type 2 diabetes, especially those who are overweight or obese. However, the extent of weight loss is generally mild, and it should not be prescribed solely for weight management [10,11]. The FDA approves metformin and has been widely used for many years. It is generally considered safe in pregnancy, but monitoring blood glucose levels closely during pregnancy is crucial, as the dosing may need adjustment. It is not typically used in children younger than 10 years old; safety and efficacy in pediatric populations require careful consideration [11]. In terms of cost, metformin is relatively affordable and available in generic formulations, making it a cost-effective option for diabetes management.

GLP-1 Agonists

Semaglutide

Semaglutide is a 31-amino acid peptide hormone that mimics native GLP-1. It resists degradation by dipeptidyl peptidase-4 (DPP- 4) and has reduced renal clearance, leading to a prolonged plasma half-life. As a GLP-1 receptor agonist (GLP-1 RA), Semaglutide regulates glucose homeostasis by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. It also delays gastric emptying and lowers both fasting and postprandial blood glucose levels, resulting in weight reduction. Semaglutide activates sites in the hypothalamus to control energy intake and reduce food cravings. The recommended dose for weight management is 2.4mg injected subcutaneously once weekly. However, it carries a black box warning against use in patients with a history of medullary thyroid carcinoma or pancreatitis, and it should not be used during pregnancy [14,15].

Liraglutide

Liraglutide is a modified GLP-1 receptor agonist that binds to serum albumin non-covalently, leading to a longer half-life of 11 to 15 hours. It enables 24-hour glycemic control with once-daily dosing. Liraglutide improves fasting and post-prandial glycemic control through increased insulin secretion, reduced glucagon levels, and minor gastric emptying delays. Additionally, it reduces appetite and energy intake and has favorable effects on postprandial lipid profiles. The FDA approved liraglutide for treating type 2 diabetes with a daily injectable dose of 1.8 mg and for chronic weight management with a 3.0 mg daily injectable dose. Liraglutide was found to reduce fasting blood glucose, hemoglobin A1c, and systolic blood pressure [16].

Exenatide

Exenatide is an incretin mimetic agent, a synthetic analog of GLP-1, derived from salivary secretions of the lizard Heloderma. As an adjunctive therapy for type 2 diabetes, exenatide improves glycemic control by stimulating glucose-dependent insulin secretion, suppressing elevated glucagon levels, delaying gastric emptying, and reducing food intake. It mainly undergoes elimination through glomerular filtration. The recommended dosing is 1.0 mg subcutaneously twice daily. Adverse events, including mild to moderate nausea, have been reported in clinical trials. Exenatide has shown significant improvements in glycemic control and modest weight loss in patients receiving add-on therapy with metformin or sulfonylurea [17,18]. Overall, these GLP-1 receptor agonists, including Semaglutide, liraglutide, and exenatide, offer effective options for the management of type 2 diabetes and weight reduction in appropriate patients, with varying dosing regimens and administration routes.

Dual GIP/GLP-1 Agonists

Tirzepatide

Tirzepatide is a synthetic peptide that acts as a dual gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP- 1) receptor agonist. It consists of 39 amino acids and stimulates insulin release from the pancreas, reducing hyperglycemia in individuals with type 2 diabetes mellitus (T2DM). Additionally, it increases adiponectin levels and lowers appetite, making it more effective in controlling hyperglycemia and inducing weight reduction compared to GLP-1 agonists alone. The drug is administered via subcutaneous injection and is available in different dosages.

The standard dosing is once weekly, starting with an initiation dose of 5 mg/0.5 mL, which can be adjusted based on efficacy and adverse effects. The most common adverse drug reactions are gastrointestinal, such as abdominal discomfort and nausea, which may influence the dosing titration based on patient tolerance. Tirzepatide is FDA-approved for T2DM treatment but not for type 1 diabetes or pancreatitis. It can also be used off-label for obesity management, similar to GLP-1 medications like Semaglutide [19- 21].

Regarding safety, Tirzepatide has been shown to be generally well-tolerated, with gastrointestinal adverse effects being the most common. Nausea, diarrhea, and decreased appetite are frequently reported, and constipation and vomiting are reported less frequently. It can also cause delayed gastric emptying, potentially affecting the absorption of other oral medications and leading to reduced efficacy of oral contraceptives. Other reported adverse effects include sinus tachycardia, acute kidney injury, hypersensitivity reactions at the injection site, and worsening of diabetic retinopathy in some patients. There is a risk of hypoglycemia, especially in patients on insulin therapy or sulfonylureas, and the drug is contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 [22-29].

Tirzepatide offers significant potential in treating T2DM and obesity, with double-digit weight loss and glycemic control seen in clinical trials. A growing body of evidence from various clinical trial programs, such as SURPASS and SURMOUNT, supports the drug’s efficacy and safety. Further research is needed to assess its long-term cardiovascular safety and effectiveness and its impact on other cardiometabolic complications in people with T2DM and obesity. The FDA has approved Tirzepatide as Mounjaro® for improving glycemic control in adults with T2DM. Still, it is not indicated for type 1 diabetes and is not recommended for use in children under 18 years old [30,31].

Regarding use during pregnancy and lactation, there is insufficient data to determine the drug-related risk for pregnant women, but animal data suggests that Tirzepatide may cause fetal harm. Therefore, its use in pregnant women is not recommended. As for breastfeeding, there is limited information on the clinical use of Tirzepatide during lactation. The drug is a large peptide molecule with low absorption potential in infants, but more data is needed to fully understand its safety during breastfeeding. Until further evidence becomes available, caution should be exercised when using Tirzepatide during breastfeeding, especially in nursing newborns or preterm infants [32].

SGLT-2 Inhibitors

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a novel class of hypoglycemic drugs that includes dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, and Sotagliflozin. These drugs work by lowering the renal glucose threshold and increasing urinary glucose excretion, thereby improving glycemic control [33]. Besides their antidiabetic effects, SGLT2i has demonstrated benefits in cardiovascular conditions such as heart failure, myocardial infarction, hypertension, cardiomyopathy, and arrhythmia [34]. Moreover, evidence supports their use in diabetic individuals with chronic kidney disease (CKD) and nondiabetic populations with CKD [35,36].

The mechanism of action of SGLT2i involves their competitive binding to SGLT2 proteins in the proximal segments (S1) of the renal tubules. The drugs reduce glucose reabsorption by inhibiting these cotransporters, increasing urinary glucose excretion and decreasing plasma glucose levels. Unlike other antidiabetic medications, SGLT2i does not stimulate pancreatic β cells to secrete insulin, making them insulin-independent and associated with a low risk of hypoglycemia. However, it’s worth noting that their efficacy may decrease in individuals with reduced renal function [37-39].

In addition to their antidiabetic effects, SGLT2i have shown beneficial effects on endovascular function by indirectly reducing oxidative stress and inhibiting proinflammatory mediators [40]. These drugs also improve myocardial metabolism by inhibiting sodium-hydrogen exchanger 1 isoform in the myocardium, reducing calmodulin-dependent kinase II activity, and enhancing mitochondrial calcium levels, ultimately improving cardiac efficiency [39-41]. Furthermore, SGLT2i have been found to improve renal function, reduce adipose-mediated inflammation and sympathetic overdrive, modulate the intrarenal reninangiotensin system, and increase erythropoietin levels, which positively impacts vascular progenitor cells [41].

Sodium-glucose cotransporter 2 inhibitors have also demonstrated significant efficacy in promoting weight loss in addition to their antidiabetic and cardiovascular benefits. This weight loss effect is particularly advantageous for individuals with obesity or overweight, making SGLT2i a favorable option for those aiming to reduce body weight [42]. The weight loss mechanism of SGLT2i is attributed to their ability to increase urinary glucose excretion. As glucose is excreted in the urine, it leads to the loss of calories, resulting in a reduction in body weight [10]. Studies have shown that treatment with SGLT2i is associated with clinically meaningful weight loss in diabetic and non-diabetic patients with obesity [42,43].

In clinical trials, SGLT2 inhibitors, such as dapagliflozin and empagliflozin, have significantly reduced body weight compared to other antidiabetic medications or placebo [43,44]. This weight loss effect can be particularly beneficial for individuals with type 2 diabetes who often struggle with overweight or obesity, as it can contribute to improved glycemic control and reduced cardiovascular risk factors [42,43]. The combination of glycemic control, cardiovascular benefits, and weight loss makes SGLT2i a valuable therapeutic option for patients with type 2 diabetes and obesity. However, it’s essential to consider individual patient characteristics and potential side effects when determining the most suitable treatment approach.

Close monitoring and personalized management are crucial to optimize the outcomes and safety of SGLT2 inhibitors in diverse patient populations [43-45]. Overall, SGLT2 inhibitors have proven to be promising medications not only for the management of diabetes but also for their beneficial effects on cardiovascular, renal, and weight loss conditions. Their unique mechanisms of action set them apart from other antidiabetic drugs and offer potential advantages in terms of safety and cardiovascular risk reduction. Further research is ongoing to explore their full potential and role in treating various metabolic and cardiovascular disorders.

Amylin Mimetics

Pramlintide

The drug is a synthetic analog of amylin, a peptide hormone produced by the pancreas. It differs from native amylin in three amino acid substitutions and is a stable and soluble analog administered via subcutaneous injection at mealtime. Pramlintide regulates post-meal blood glucose levels by slowing gastric emptying, suppressing abnormal postprandial glucagon secretion, and promoting satiety, which leads to reduced caloric intake [46-50]. The glucose-dependent mechanism of pramlintide prevents hypoglycemia without therapies that cause it and helps exogenous insulin therapy better match physiologic needs.

The drug is only approved for use in patients with type 1 and type 2 diabetes who are taking prandial insulin. Dosing varies depending on the type of diabetes, and patients may require adjustments in pre-meal insulin doses to achieve euglycemia. The primary adverse events associated with pramlintide are nausea, vomiting, and anorexia, which are more common in patients with type 1 diabetes and tend to diminish over time. There is an increased risk of severe hypoglycemia, especially in patients with type 1 diabetes, when pramlintide is started at full doses without reducing insulin doses. Pramlintide has also been associated with migraine-like symptoms, likely due to the activation of amylinresponsive receptors in various body parts [47-54].

One significant benefit of pramlintide therapy is its association with weight loss. Clinical studies have shown that improved glycemic control with pramlintide is correlated with sustained and significant reductions in body weight. The drug induces satiety and decreases caloric intake, possibly contributing to weight loss. In combined data from pramlintide clinical trials, patients with type 1 diabetes experienced weight reductions of approximately 1.5 kg at 25 weeks, while patients with type 2 diabetes saw reductions of 1.2 kg compared to placebo-treated patients, who had slight weight gains.

Weight reductions were sustained for up to 52 weeks in longterm trials for both types of diabetes [50-56]. Regarding lactation, pramlintide has a high molecular weight and a short half-life, making it unlikely to pass into breast milk in clinically significant amounts. Additionally, it is a peptide likely to be digested in the infant’s gastrointestinal tract, further reducing the potential for reaching clinically important levels in the infant’s serum. However, since there is limited information on using pramlintide during breastfeeding, an alternate drug may be preferred to ensure the safety of the nursing infant [57,58].

Gastric Bypass Surgery

Gastric bypass surgery involves creating a small stomach reservoir and a gastrojejunoanastomosis using a defunctionalized Roux Y loop to alter digestion. It is recommended as an option for the treatment of type 2 diabetes in selected surgical candidates with a BMI ≥40 kg/m² (or ≥37.5 kg/m² in Asian individuals) and in adults with BMIs between 35.0 and 39.9 kg/m² (or 32.5– 37.4 kg/m² in Asian Americans) who have not achieved lasting weight loss or improvement in comorbidities with non-surgical methods. Metabolic surgery may also be considered for adults with a BMI of 30.0–34.9 kg/m² (or 27.5–32.4 kg/m² in Asian American individuals) who have not succeeded with non-surgical methods [59]. While there are no absolute contraindications to bariatric surgery, relative contraindications exist. These include severe heart failure, unstable coronary artery disease, end-stage lung disease, active cancer treatment, portal hypertension, drug/ alcohol dependency, impaired intellectual capacity, and Crohn’s disease, in the case of LRYGB. Additionally, gastric bypass surgery is generally contraindicated in patients with uncontrolled medical conditions such as severe cardiovascular disease, uncontrolled hypertension, or uncontrolled diabetes. Patients with active substance abuse and severe mental health disorders may not be suitable candidates due to hindrances in post-operative recovery and adherence to lifestyle changes. Pregnant or planning pregnant women, individuals with previous gastrectomy or bowel resection, young adolescents, and patients at high surgical risk may also not be ideal candidates for the procedure [60].

Studies have demonstrated the efficacy of gastric bypass surgery in weight loss for individuals with a BMI greater than 35 kg/m² and those with a lower BMI. Randomized clinical trials and observational studies have shown significant weight loss in gastric bypass groups compared to non-surgical treatment groups. The surgery has also been associated with superior glycemic control, cardiovascular risk reduction, decreased incidence of microvascular diseases, improved quality of life, and reduced risk of cancer and other associated risks. Gastric bypass surgery has been found to lower triglyceride levels, increase high-density lipoprotein (HDL) cholesterol, and reduce the need for insulin in type 2 diabetes patients [61-64]. In some cases, metabolic surgery has shown potential benefits for individuals with type 1 diabetes, but larger and longer studies are needed to confirm its role in these cases. Despite the high initial costs, some analyses have suggested that metabolic surgery may be cost-effective for people with type 2 diabetes, depending on assumptions about its long-term efficacy and safety [65]. Overall, gastric bypass surgery appears to be a valuable treatment option for selected individuals with obesity and type 2 diabetes, offering significant weight loss, improved metabolic profiles, and reduced cardiovascular risks [66].

Conclusion

The treatment of weight loss in individuals with diabetes requires a comprehensive approach. Pharmacological interventions, such as metformin, GLP-1 receptor agonists, SGLT- 2 inhibitors, and amylin mimetics, can play a significant role in weight reduction and glycemic control. Additionally, dual GIP/ GLP-1 agonists, such as tirzepatide, demonstrated significant potential in treating type 2 diabetes and obesity, offering considerable weight loss and glycemic control. However, further research is needed to assess their long-term cardiovascular safety and the impact on other cardiometabolic complications.

Gastric bypass surgery is a valuable treatment option for selected individuals with obesity and type 2 diabetes, offering significant weight loss and improved metabolic profiles. It has been associated with superior glycemic control, cardiovascular risk reduction, and improved quality of life. However, it is essential to carefully select suitable candidates for surgery and consider potential contraindications and risks. Personalized treatment plans, lifestyle modifications, and continued research are needed to optimize outcomes and improve management strategies for weight loss in individuals with diabetes.

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