This purpose of this article is to bring awareness to women who experience perinatal depression, as well as women who experience postpartum depression, up until the first year, after giving birth, and how these depressive symptoms affect not only the mother, but also, the fetus in utero, and the child, all throughout the life stages of development (infancy, childhood, adolescence, and adulthood). It also serves to give interventions to nurses who work closely with patients who are experiencing depression, or who are at risk.

Perinatal depression can have a range of symptoms and emotions which can be classified as mild or severe. It can affect any woman, but higher rates have been found in women who come from a low socioeconomic background, as well as women who have faced major life stressors and who have a history of mental illness. Women who experience depression during pregnancy tend to forget to care for themselves, they are also more likely to have pre-term babies, or babies with low birth weight. Their depressive state can cause them not to take safety precautions in regards to the infant (Goodman, 2019).

During the early infant/early child hood stage, a child learns to develop loving bonds with those around them, especially the caregiver. They should feel emotionally secure, and have their need met. In the first year of a child is a very important time, because there is a lot of cognitive growth taking place, if nurtured in a healthy way. Because newborns of depressed mothers may not get lot of healthy maternal-infant interaction, they tend to have problems with sleeping and difficult temperaments (Goodman, 2019).

Research shown that there is a correlation between the levels of the stress hormone, cortisone, and the neurotransmitter, serotonin of depressed pregnant women on the fetus. If fetus receives an excessive amount of both cortisol and serotonin. This results in the child being at risk for mental health disorders and behavioral issues (Goodman, 2019).

Depressed women who fail to display any sort of positive facial expressions or affection, toward their baby tend see their infant exhibit similar dysfunction.  The baby’s response in turn affects the depressed mother, who begins to feel even more depressed. This dysfunction also sets the kid up for behavior issues later on in life (Goodman, 2019). Not all children of depressed mother have been affected negatively. It really depends on the severity of depression. It has been shown that the children of women who have been depressed all throughout their pregnancy, was negatively affected more (Goodman, 2019).

Both pharmacological and non-pharmacological treatments exist for women who are pregnant and have depression. Most women prefer non-pharmacological means of controlling depression because research is unclear on the effects that medication for depression has on the fetus. Psychotherapy is the first line of treatment, followed by medication, if psychotherapy is not sufficient (Goodman, 2019).

Most of research have been geared towards women who have experienced perinatal depression, but not enough research has been focused on how the child the depressed mother is affected. There now exists research that aims to provide interventions to not only provide the mother with support to ameliorate the effects of depression, but to improve the mother-infant interaction (Goodman, 2019).

There are several interventions that nurses can implement to help women cope with depression during pregnancy. Psychiatric nurse practitioners need to be trained and help clients who are at risk for and suffer from depression develop a plan for their mental well-being. The psychiatric nurse practitioner should be trained on perinatal depression, both pharmacological and non-pharmacological means of treatment available, and be trained on infant development and child parenting. Routine screenings of depression should be conducted at every prenatal visit. For patients who doesn’t have access to treatment, there needs to be alternatives set in place to assure that the patient gets the help that they need. Because maternal depression affects children, there needs to be more teaching geared to help prepare patients for parenthood. Nurses should also encourage patients to bring their infant to their visits to observe how the mothers interact with their child. This is helps he care provider screen for potential symptoms of depression (Goodman, 2019).

Perinatal depression has a negative impact on patient care when untreated. There are women that suffer in silence because there are not enough routine screenings to detect depression before and during their pregnancy, as well as interventions set in place to provide relief. This negatively affects the fetus in utero, infant, and child, emotionally, socially, and cognitively. With routine screening, and intervention are set in place, it benefits both the mother and the child.

Reference:

• Goodman, Janice H. (2019). Prenatal depression and infant mental health.
  
  Archives of Psychiatric Nursing
  
  ,
  
  33
  
  (3), 217-224. Doi: http://dx.doi.org/10.10161j.apnu.2019.01.010

Introduction

Anxiety is an alter psychological, physiological, and behavioral state which is characterized by hyperarousal, neuroendocrine modulation and a series of behavior transition as a response of potential danger, like perceiving imminent death and low ego integrity [

1

]. This functional and behavior changes are helpful to counteract such threat. However if the state of anxiety, exceed and persist for prolong time than it will transform into pathological state which has negative consequences on well being and social life [

2

,

3

]. Anxiety disorders are one of the most debilitating and the most commonly occurring psychiatric disorder, affecting nearly 10 to30% of the society [

4

,

5

]. Overgeneralized anxiety can be frustrating as it can impair the quality of life [

6

]. Various co-morbidity features associated with anxiety are anhedonia, restlessness, fatigue and poor performance. Successful therapy like benzodiazepines has been introduced into clinical practice, however still development of new and better anxiolytics is one of the major areas of scientific interest [

7

]. A lot of patients with anxiety respond inadequately to the current existing interventions. Therefore researchers always strive to develop new drugs with greater efficacy and least side effects.

Testicular torsion is an emergency condition which occurs due to twisting of the spermatic cord. It halts the blood supply to testicles and provokes ischemia, eventually leads to severe pain. Apart from it, testicular reperfusion also precipitate oxidative stress which plays a vital role in leydig cell dysregulation,

conclusively

results to germs cell apoptosis.

As it is notably, a bimodal incidence in adolescents and neonates, therefore it need prompt attention to avoid testicular loss and infertility in such age groups[

8

]. If the ongoing process is untreated it leads to loss of spermatogenesis and depletion of fertility. The main pathophysiology of this particular condition seems to be testicular Ischemia Reperfusion (IR) injury, mediated by burden of free radicals. This condition puts the seminiferous tubules on the borderline of hypoxia and susceptible to reduction in blood flow, so the ischemia/reperfusion injury causes degeneration of germ cells and loss of spermatogenesis[

9

].

As pain is one of the main side effects associated with testicular torsion therefore it is usually accompanied by medical conditions such as anxiety. Also low testosterone level has been implicated that it converts into active metabolite in the brain that interacts with GABAa receptor and therefore reduce anxiety[

10

,

11

] . Another laboratories further demonstrated that both dihydrotestosterone and 3α-androstanediol have the potential to relieve anxiety like behavior in male rats[

11

,

12

]. Another set of researchers finally acknowledged that one of the hallmark of low testosterone level in men with andropause is anxiety[

13

]. In another study in humans they reported that boys presenting low testosterone level are more prone to anxiety and other mental problems such as depression and attension [

14

]. Therefore the low level of testosterone due to testicular torsion is an important element to be considered in the initiation of mood disorders like anxiety, anger, aggression and hostility.

On the other hand, testicular torsion/detorsion pain is a psychosomatic disorder which induces anxiety. Because testicular torsion is a potentially reversible condition if diagnosed and treated earlier. Much work needs to be done to clarify the interpretation of such phenomena in the course of anxiety.

Minocycline is a semisynthetic broad spectrum second generation tetracycline that is widely distributed into blood-brain barrier. Aside from its antimicrobial activity it exhibit a wide array of effects in Alzheimer’s disease,

Huntington disease

, Amyotrophic Lateral Sclerosis (ALS), Parkinson’s disease (PD), Multiple sclerosis (MS), as well as stroke[

9

,

15-17

].

It also display neuroprotective effects against cerebral ischemia, and vascular dementia in various animal models and has a role in alleviating inflammation[

18

]. It has been reported that minocycline effects behavior and mental disorders like cognition and psychotic disorders, and Schizophrenia [

19

,

20

].

Nitric oxide(NO) is one of the exceptional-free radical gaseous signaling molecule, involved in many physiological and pathological signaling[

21

]. NO depict its role in various behaviors like memory, pain, scratching, sleep, depression and anxiety [

22-27

]. The involvement of NO in anxiety can be attributed to its modulatory effect on serotonin,

melanin-concentrating hormone, Testosterone level in bran

[

28

].

L-arginine/NO/cGMP pathway is elaborated in various physiological functions [

29

]. Phosphodiesterase type 5 (PDE5) inhibitors augment the cGMP bioavailability which is a downstream effector of NO. Thus it intensify the biological effects mediated by NO[

30

]. It has also been found that NOS inhibitors have anxiolytic effects by declining cyclic guanosine monophosphate (cGMP) and NO levels[

31

,

32

]

Regarding the neuroprotective effects of minocycline and the role of NO in the context on behavioral disorders, in the present study we investigated the hypothesis that acute minocycline administration has potential anxiolytic action in the male rats that underwent testicular torsion/detorsion operation followed by elevated plus maze test. Also this effect is partly exerted through the L-arginine/NO/cGMP signaling pathway.

Materials and Methods

Animals

Animal models are certainly one of the useful and valid model for the investigation of human disease like anxiety disorder. Male adult Sprague-Dawley mice weighing 150–250 g were housed and used. All animals were handled and used during the experiments in accordance with the principles of institutional laboratory animal care and regulations committee (Experimental medicine research center, department of pharmacology, School of Medicine, Tehran University of Medical Sciences) guidelines. The animals were housed in cages maintained at constant temperature of 21–23

^â-¦

C and humidity on a 12-h regular light-dark cycle (lights on at 07:00-19:00 h). Food and water were available ad libitum except for short period in which they were used for testicular torsion/detorsion and for behavioral test. All behavioral experiments were conducted between 12:00 and 18:00 h. The rats were categorized into 4 main groups: un-operated control, sham-operated, underwent testicular torsion/detorsion receiving vehicle, and testicular torsion/detorsion receiving drug. The study was approved by the Ethics Committee of Tehran University of Medical Sciences.

Testicular Torsion/Detorsion

All experiments were made under sterile conditions. Animals were anesthetized using i.p injection of ketamine HCl (50 mg/kg) and chlorpromazine (25 mg/kg). After induction of anesthesia, , the skin of scrotal zone was exposed for aseptic surgery (a 10% povidene-iodine scrub followed by a sterile saline wipe)by shaving. According to Turner et al a standard scrotal incision was made for experimental induction of 1h testicular torsion right testis of mice [

33

]. After the incision, tunica vaginalis was opened and the testis was torsioned (720° in the clockwise direction) and maintained in twisted position. The testis was kept away from drying using sterile gauze soaked with normal saline. After appropriate time, the testis was reposition by counter-rotating to its normal form, followed by reinsertion of the testis into the scrotum via the inguinal canal. After surgery the scrotum skin incision was sutured (4-0 nonabsorbable). In the sham-operated animals, the spermatic cord were just retracted and replaced. All behavioral tests were performed after recovery period at day 30.

Testosterone assay

At day 30, the mice were anesthetized with i.p injection of ketamine HCl (50 mg/kg) and chlorpromazine (25 mg/kg), and then were injected 0.1 mL heparin i.v (1000 U/mL; Solopak, Elk Grove Village, Ill). Blood samples were collected via testicular venous from the contralateral, sham-operated testis. As a terminal procedure after that the mice in the experimental groups were subjected to CO

₂

for sacrifice. The collected blood samples were centrifuged at 5000 rpm at 0 â-¦C for 15 min, and then stored at-20°C until an assay for testosterone by RIA kits (TTKT kits, Siemens Inc.) was performed. The testicular venous plasma testosterone (TVT) concentrations were also determined for unoperated, control animals in the same manner.

Open-field test

The Open Field Test (OFT) is one of the valid experimental tests used to evaluate general locomotor activity and anxiety in rodents of

scientific research

[

34

]. It consist of a Plexiglas box scaled 1 m × 1 m, under dim light to avoid anxiety behavior. The animals were placed in the arena which is divided into 12 equal squares. Each rat was placed individually and was allowed to freely move about for 10 minutes while being recorded by an overhead camera. Rat behaviors were recorded by a digital camcorder and were analyzed for open field. Total duration spent in the center was analyzed in EthoVision XT version 6 (Noldus Information Technology, Leesburg, VA). After utilizing the apparatus for individual rat it was cleaned with a solution of 10% ethanol for second use in order to hide animal clues.

Elevated plus maze (EPM)

The elevated plus-maze (EPM) apparatus is used to assess anxiety-related behavior in rodent models[

35

]. EPM apparatus consist of “+”-shaped maze elevated, oppositely positioned closed arms, two oppositely positioned open arms (enclosed by walls 40 cm high) arms measuring 50 cm × 10 cm, except for the entrance central area. The four arms delimited a central area of 10 cm

²

. The rats were placed in the apparatus and were allowed to move freely so as to explore the maze for 10 min. Rat behavior was recorded by means of digital camcorder camera mounted directly above the elevated plus maze. Entry into an arm was scored by placing all four paws within that arm. The times for The preference for being in open arms over closed arms were calculated and analyzed by EthoVision XT version 6 (Noldus Information Technology, Leesburg, VA) to measure anxiety-like behavior. The time score were calculated in percentage (open/open + closed) values (% open arms time, %OAT). Each animal was tested and observed only one time in the plus-maze apparatus. After each individual test, the apparatus was cleaned with 70% ethanol solution to hide animal clues and was totally dried before the next animal to be tested.

Drugs and Treatment

The following compounds were used in these experimental protocols: Minocycline ( ); N

^ω

-nitro-L arginine methyl ester (L-NAME), a non-specific NOS inhibitor; L-arginine, a NO precursor (Sigma, St. Louis, MO, USA). Drugs solutions were freshly prepared in physiological saline. Compounds administered i.p. was in a constant volume of 10 ml/kg body weight.

To find out the effect of surgery, the immobility time was compared with a sham-operated control group (n=6) and an unoperated group (n=6) in which normal saline was injected as the vehicle. In order to evaluate the effects of minocycline (40, 80, and 160 mg/kg, i.p.) on rats that underwent testicular torsion/detorsion, the drug was administered 4 h before the open-field test and EPM to the experimental groups (n=6). the time interval between drug administration and EPM and doses of Minocycline were selected based on our pilot study.

The anxiolytic effect of L-NAME was evaluated, by using the sub-effective doses of the non-selective NOS inhibitor. L-NAME (10 and 30 mg/kg) administered 45 min before EPM. The anxiolytic activity of minocycline and the possible involvement of NO was studied by co-administration of L-NAME (10 mg/kg) with sub-effective dose of minocycline (40 mg/kg) 45 min before EPM.

The effect of L-arginine, an NO precursor in non effective dose of 750 mg/kg was used to evaluate the anxiolytic effect of a potent dose of minocycline in the EPM. To do this, L-arginine was administred 30 min prior to the administration of minocycline.

EPM was carried out 4 h after the administration of minocycline in various experimental groups.

Statistical analysis

All data were expressed as mean ± S.E.M. and were analyzed using Sigma Plot statistical software (version 12.0). Data were interpreted by one-way and two-way analysis of variance (ANOVA) followed by TUKEY post test. A value of P<0.05 was considered as statistically significant.

Type 1 diabetes is one of the most common chronic childhood illnesses, affecting 18 to 20 per 100 000 children a year in the United Kingdom. The term type 1A diabetes for immune mediated diabetes with its destruction of the islet β cells of the pancreas.2 Non-immune mediated diabetes with severe insulin deficiency is termed type 1B. At present, the development of type 1 diabetes is a life sentence to a difficult therapeutic regimen that is only partially effective in preventing acute and chronic complications.

However, because hormone replacement with insulin therapy is sub-optimal,

acute and long-term complications are endemic despite the implementation of lifestyle and other disease management measures.

Type 1 diabetes is fatal unless treated with insulin. Injection is the most common method of administering insulin; insulin pumps and inhaled insulin have been available at various times. Pancreas and islet transplants have been used to treat type 1 diabetes; however, islet transplants are currently still at the experimental trial stage.[4]

Background

Type-1 Diabetes has been conventionally managed by twice daily insulin. While this is convenient from administration point of view, the level of insulin achieved was not physiological, owing to the characteristics of the types of insulin used, and sometimes pose difficulty in food habit and exercise pattern especially in a young child. Rapid-acting analogue insulin, on the other hand, is more physiological, and can be better suited for the patient’s needs as well as food habits.

Current practice:

Children and young people with suspected type 1 diabetes should be offered immediate (same day) referral to a multidisciplinary paediatric diabetes care team that has the competencies needed to confirm diagnosis and to provide immediate care.

At the time of diagnosis, children and young people with type 1 diabetes should be offered home-based or inpatient management according to clinical need, family circumstances and wishes, and residential proximity to inpatient services. Home-based care with support from the local paediatric diabetes care team (including 24-hour telephone access to advice) is safe and as effective as

inpatient initial management1

Insulin regimens

While the insulin regimen should be individualised for each patient, three basic types of insulin regimen can be considered2.

One, two or three insulin injections per day: these are usually injections of short-acting insulin or rapid-acting insulin analogue mixed with intermediate-acting insulin.

Multiple daily injection regimen: the person has injections of short-acting insulin or rapid-acting insulin analogue before meals, together with one or more separate daily injections of intermediate-acting insulin or long-acting insulin analogue.

Continuous subcutaneous insulin infusion (insulin pump therapy): a programmable pump and insulin storage reservoir that gives a regular or continuous amount of insulin (usually in the form of a rapid-acting insulin analogue or short-acting insulin) by a

subcutaneous needle or cannula3.

Insulin preparations

Different types of insulin are available for use in the insulin regimens for type 1 diabetes. They work for different lengths of time when injected subcutaneously. The appropriate insulin with its particular absorption profile should be matched to the person’s needs in an attempt to obtain normal to near-normal blood glucose control.

The main categories of insulin are:

• rapid-acting insulin analogues: these aim to work like the insulin normally produced to cope with a meal; they have an onset of action of approximately 15 minutes and a duration of action of 2-5 hours.

• short-acting insulins: these work more slowly than rapid-acting insulin analogues; they have an onset of action of 30-60 minutes and a duration of action of up to 8 hours

• intermediate-acting insulins: these have an onset of action of approximately 1-2 hours, maximal effects between 4 and 12 hours and a duration of action of 16-35 hours

• long-acting insulin analogues: these can last for a longer period than intermediate-acting insulins; they are normally used once a day and achieve a steady-state level after 2-4 days to produce a constant level of insulin3.

Methods of delivering insulin:

Children and young people with type 1 diabetes should be offered a choice of insulin delivery systems that takes account of their insulin requirements and personal preferences.

Monitoring glycaemic control:

Children and young people with type 1 diabetes and their families should be informed that the target for long-term glycaemic control is an HbA1c level of less than 7.5% without frequent disabling hypoglycaemia and that their care package should be designed to attempt to achieve this.

Children and young people with type 1 diabetes and their families should be encouraged to perform frequent blood glucose monitoring as part of a continuing package of care

that includes dietary management, continued education and regular contact with their diabetes care teams.

In our own trust, we have 58 children diagnosed with type 1 diabetes. 46 of them are on multi dose regime and 12 on twice a day insulin. An retrospective audit was conducted looking at the HbA1C control over a period of 12 months and associated complications. The average HbA1C of children on multi dose regime was 8.2 while that on twice a day was 9.6. Complications with hyper cholestrenemia and microalbuminuria was noted in 3 children on twice daily insulin as compare with 2 on multi dose regime. Diabetic retinopathy changes in 2 children and necrobiosis lipodica in one child on twice daily insulin.

We are now encouraging all newly diagnosed diabetic children to start on multi dose regeime from the begining. Have developed proforma for the diabetic clinic to emphasise the importance of regular investigations and scrrening procedures in the prevention of compications. We would try to reaudit in a years time to complete the audit cycle and to improve the HbA1C levels in our children.

Review of literature

Target glucose levels

The fact that chronic hyperglycemia is associated with an increased risk of microvascular complications of type 1 diabetes was demonstrated in the Diabetes Control and Complications Trial (DCCT)4.

In that trial, intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, micro-albuminuria, proteinuria, and neuropathy, as assessed over the period of 7 years.

The subsequent Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrates that benefit has continued since the DCCT trial ended in 1993.5  Not only do benefits include continued reductions in the rates of microvascular complications, additionally significant differences in cardiovascular events and overall mortality emerged. These benefits occurred in spite of the fact that subjects in the intensively treated group and those in the standard treatment group maintained similar A1C levels (approximately 8%) starting one year after the formal trial ended. Therefore, it is postulated that a “metabolic memory” exists, and that better early glycemic control sets the stage for outcomes many years in the future.

Although tight glycemic control is beneficial, an increased risk of severe hypoglycemia accompanies lower blood glucose levels. For many, the A1C target should be <7%, with premeal blood glucose level of 80-130 mg/dL. However, targets should be individualized. Individuals with recurrent episodes of severe hypoglycemia, CVD, advanced complications, substance abuse, or untreated mental illness may require higher targets, such as an A1c of <8% and preprandial glucose levels of 100-150 mg/dL.

Self-monitoring of glucose levels

Optimal diabetic control requires frequent self-monitoring of blood glucose levels. Frequent monitoring allows for rational adjustments in insulin doses. Most patients with type 1 diabetes require 2 or more injections of insulin daily with doses adjusted based on self-monitoring of blood glucose levels. In general, individuals with type 1 diabetes should test a minimum of 4 times per day-before each meal and at bedtime.

Subcutaneous continuous glucose sensors are now available, making the continuous glucose monitor (CGM) possible. These devices measure interstitial glucose levels every 1-5 minutes, providing alarms when glucose levels are too high or too low or are rapidly rising or falling.

CGM transmits to a receiver, which is either a pager like device or is integral to an insulin pump. Looking at the continuous glucose graph and responding to the alarms can help patients avoid serious hyperglycemia or hypoglycemia.

Several drawbacks exist:

first, there is a lag between glucose levels in the interstitial space and capillary blood, so the levels recorded by the CGM may differ from a finger stick glucose.

For that reason, the trends tend to be more helpful. Second, patients may over treat hyperglycemia (repeatedly giving insulin because the glucose levels do not fall rapidly enough-a phenomenon known as stacking) as well as over treat lows (the glucose levels rise slowly with ingestion of carbohydrate).

Patients using CGM and/or insulin pumps can often provide very detailed information as to their insulin regimens as well as recent alterations in blood glucose levels.

Types of insulin

By definition, patients with type 1 diabetes require lifelong treatment with insulin to promote glucose utilization. Rapid-, short-, intermediate-, and long-acting insulin preparations are available. Although pork, beef, and beef-pork insulins were previously used, recombinant human insulin is used almost exclusively in the United States. Commercially prepared mixtures of insulin are also available.

Insulin is sensitive to heat and exposure to oxygen. Once a bottle of insulin is open, it should be used for no more than 28 days and then discarded, even if insulin remains in the bottle. Use of old insulin can result in a lack of clinical effectiveness. Insulin in a pump reservoir for longer than 3 days may lose its clinical effectiveness (although insulin aspart has now been approved for use for up to 6 days in a pump). Sometimes, insulin distributed from the pharmacy has been exposed to heat or other environmental factors and may be less active. If a patient is experiencing unexplained high blood sugar levels, new insulin vials should be opened and used.

Common insulin regimens

Although emergency physicians rarely start new therapy for patients with diabetes, being acquainted with the various forms of insulin and the common regimens is useful.

When treating patients with type 1 diabetes, the goal is to provide insulin in a manner that is as physiologic as possible. Insulin replacement is given as a basal insulin (either long-acting [glargine or detemir] or intermediate-acting [NPH]) and preprandial (premeal) insulin (either rapid-acting [lispro, aspart, or glulisine] or short-acting [regular]). For patients on intensive insulin regimens (multiple daily injections or insulin pumps), the preprandial dose is based on the carbohydrate content of the meal (the carbohydrate ratio) plus a correction dose if their blood glucose level is elevated (eg, 2 additional units of rapid-acting insulin to correct the blood glucose from a level of 200 mg/dL to a target of 100 mg/dL). This method allows patients more flexibility in caloric intake and activity, but it requires more blood glucose monitoring and attention to the control of their diabetes.

Common insulin regimens include the following: (1) split or mixed, such as NPH with rapid-acting (eg, lispro, aspart, or glulisine) or regular insulin before breakfast and supper; (2) split or mixed variant: NPH with rapid-acting or regular insulin before breakfast, rapid-acting or regular insulin before supper, NPH before bedtime (designed to reduce fasting hypoglycemia by giving the NPH latter in the evening); (3) multiple daily injections (MDI), a long-acting insulin (eg, glargine or detemir) once a day in the morning or evening (or twice a day in about 20% of patients), and a rapid-acting insulin before meals or snacks (dose adjusted based on the carbohydrate intake and the blood glucose level); and (4) continuous subcutaneous insulin infusion (CSII), rapid-acting insulin infused continuously 24 hours a day through an insulin pump at one or more basal rates, with additional boluses given before each meal, and correction doses administered if blood glucose levels exceed target levels.

Rapid-acting injectable insulins

With the most rapid onset of action, these insulins are used whenever a rapid onset and short duration is appropriate (eg, before meals or when the blood glucose level exceeds target and a correction dose is needed). Rapid-acting insulins are associated with less hypoglycemia than regular insulin.

Insulin aspart (NovoLog)

Onset of action is 5-15 min, peak effect is in 30-90 min, and usual duration of action is 4 h. Has FDA approval for use in insulin pumps

Doses vary; adjust dose according to patient’s metabolic needs; adjust to achieve premeal and bedtime blood glucose levels of 80-140 mg/dL (children <5 y, 100-200 mg/dL)

Insulin glulisine (Apidra)

Onset of action is 5-15 min, peak effect is in 30-90 min, and usual duration of action is 4 h. Has FDA approval for use in insulin pumps.

Individualize dose; intended for intermittent SC injection with meals or use by external infusion pump

Insulin lispro (Humalog)

Onset of action is 5-15 minutes, and usual duration of action is 4h.

Doses vary; adjust dose according to patient’s metabolic needs; titrate to maintain a premeal and bedtime glucose of 80-140 mg/dL

Short-acting injectable insulins

Currently, short-acting insulins are less commonly used than the rapid-acting insulins in patients with type 1 diabetes. They are used when a slightly slower onset of action or greater duration of action is desired.

Intermediate-acting injectable insulins

With their relatively slow onset of action and relatively long duration of action, these insulins usually are combined with faster-acting insulins to maximize benefits of a single injection.

Insulin NPH (Humulin N, Novolin N)

Onset of action 3-4 h, peak effect in 8-14 h; usual duration of action 16-24 h. Appears cloudy. Must be gently mixed and checked for clumping; if clumping occurs, the insulin should be discarded.

Long-acting injectable insulins

These insulins offer a long duration of action and are effective basal insulins. In patients with type 1 diabetes, they must be used in conjunction with a rapid-acting or short-acting insulin given before meals.

The US Food and Drug Administration (FDA) has issued an early communication to health care practitioners regarding 4 recently published observational studies that describe the possible association of insulin glargine (Lantus) with an increased risk of cancer.28 Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.

The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than what is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raise further questions about the risk that actually exists and therefore warrants further evaluation.

The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

Insulin detemir (Levemir)

The package insert states the duration of action ranges from 5.7 h (low dose) to 23.2 h (high dose), but, in clinical practice, the duration of action is similar to insulin glargine.29

Insulin glargine (Lantus)

Onset of action 4-6 h, generally no discernible peak effect, but an increased effect may occur at 10-20 h; usual duration of action 24-28 h.

Genes

Alleles or genetic variants associated with type 1 diabetes provide either susceptibility to or protection from the disease. An interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for disease and provides potential targets for both prediction and prevention of disease6 . The concordance for type 1 diabetes is approximately 50% for monozygotic twins, and the risk to a first degree relative is approximately 5%7 . The major genetic determinant of susceptibility to diabetes lies within the major histocompatibility complex (termed IDDM 1). More than 90% of patients who develop type 1 diabetes have either DR3, DQ2 or DR4, DQ8 haplotypes, whereas fewer than 40% of normal controls have these haplotypes.6 DR3-DR4 heterozygosity is highest in children who develop diabetes before age 5 (50%) and lowest in adults presenting with type 1 diabetes (20-30%), compared with a US population prevalence of 2.4%. Only one non-HLA gene has been identified with certainty-IDDM 2 on chromosome 11p5.5-and this contributes about 10% of the familial aggregation of type 1 diabetes. This locus is a polymorphic region that maps to a variable number of tandem nucleotide repeats (VNTR) 5′ of the insulin gene. Studies in man indicate that different sizes of this VNTR 5′ of the insulin gene are associated with risk for type 1 diabetes. The long form of the VNTR (> 100 repeats, class III) is associated with protection from diabetes. This influence of the insulin gene locus may relate to variation in expression of insulin within the thymus (greater thymic insulin message with protective VNTR). 1 shows a summary of the susceptibility loci for type 1 diabetes.

Epidemiology

Although most attention has focused on the increase in type 2 diabetes, a parallel rise in type 1 diabetes has occurred8 .

Type 1 diabetes has always been known as a disease of childhood, but more recent epidemiological studies have indicated that the incidence is comparable in adults9. The enormous international variation in incidence is now recognised. A child in Finland is almost 40 times more likely to develop type 1 diabetes than a child in Japan and almost 100 times more likely to get the disease than a child in the Zunyi region of China10 . The EURODIAB collaborative study, a registry involving 44 countries in Europe, indicates an annual rate of increase in incidence of type 1 diabetes of 3-4%, with a larger increase in some central and eastern European countries 11. The largest rate of increase is seen in children aged 0-4 years. Type 1 diabetes is associated with other autoimmune conditions; the most common association is with thyroid disease12. The Belgian Diabetes Registry indicated that the prevalence of thyroid peroxidase autoantibodies is 22% in patients with type 1 diabetes. Approximately 1 in 10 patients with type 1 diabetes express transglutaminase IgA autoantibodies, and more than half of these patients have coeliac disease on intestinal biopsy. Approximately 1 in 50 people with type 1 diabetes have 21-hydroxylase autoantibodies, and approximately 25% of these patients progress to Addison’s disease

Prevention and new treatments

To date no treatment has been shown to prevent type 1 diabetes in humans. More than 100 different treatments prevent type 1 diabetes in the NOD mouse model, and this may indicate that disease prevention in this model is “too” easy.28 Two major trials have been conducted to try to prevent type 1 diabetes. In the United States, the diabetes prevention trial (DPT-1) was started in 1994 with the aim of determining whether antigen based treatment with insulin (oral and parenteral insulin treatment in relatives at high and moderate risk) would prevent or delay diabetes. These treatments did not overall slow the progression to diabetes. The European nicotinamide diabetes intervention trial (ENDIT) also found no difference in protection from diabetes when participants were assigned to either oral nicotinamide or placebo treatment (P Bingley, European Association of the Study of Diabetes, Budapest, September 2002). Many challenges remain in this field; in particular assays for pathogenic human T cells are not yet available. Such assays have the potential to provide surrogate markers to guide evaluation of immunotherapy; in the absence of such markers, the primary outcome of trials today is the preservation of insulin secretion (for example, measurement of C peptide secretion). TrialNet and the Immune Tolerance Network created by the US National Institutes of Health will be focusing not only on the prevention of diabetes but also on preventing further loss of islet βcells in patients with new onset type 1 diabetes.

Insulin remains the main treatment in type 1 diabetes. The diabetes control and complications trial (DCCT) showed the importance of strict metabolic control in delaying and preventing complications.29 The risk of hypoglycaemia is still the major limiting factor in achieving euglycaemia with insulin treatment. The introduction of rapidly absorbed insulin analogues has reduced variability of insulin absorption and allows insulin administration in young children after meals.30 Another recent introduction to the insulin market has been insulin glargine, which functions as a very long acting insulin (peakless basal insulin).31Combinations of engineered very long acting insulins and rapid acting insulins can provide control and convenience similar to that obtained with insulin pumps.

The use of metformin treatment alongside insulin has increased in patients with type 1 diabetes. Recent studies have suggested that metformin might benefit type 1 diabetes patients who are overweight, are receiving large doses of insulin, or have an HbA1c > 8%.32 The coexistence of insulin resistance in patients with type 1 diabetes is a new area of interest. Islet transplantation with modified immunosuppressive regimens can cure type 1 diabetes. Islet transplantation is a consideration for the limited but important subset of patients with recurrent severe hypoglycaemic episodes not responsive to medical management.33 Inability to control autoimmunity and alloimmunity and a lack of donor organs limit the application of islet transplantation.

Summary & conclusion:

DCCT trial was a landmark trial based on 1441 volunteers over a period of 10 years( 1983-1993). The study showed the importance of keeping glucose levels as close to normal ( physiological levels). This study was conducted over 29 medical centres based in USA and Canada.

Multicentre studies over the last two decades have shown that MDI are better than twice a day insulin regimes. The main issues with twice daily insulin injections were having high HbA1C levels, which in turn led to long term complications:

There was early development of hyper cholestrenemia, diabetic retinopathy, micro vascular renal disorder and peripheral neuropathy.

The second main issue with twice a day insulin regime was children’s lifestyle had to be quite rigid since they had to wake up every morning to have their insulin, have their breakfast, then have a mid day snack, later lunch, post lunch snack, tea with their evening insulin and later another snack before going to bed. This also led to obesity, over weight and other complications associated with it.

Given the need for sticking to a rigid diet, which often was not possible, lead to fluctuating intake, leading to a fluctuating glucose levels.

With multiple daily regime, the child is noted to have better quality of flexible lifestyle, the insulin and glucose control is more physiological. Their diet can be more variable, no need to snack in-between meals, less long term complications and better control of HbA1C noted.

The only drawback of multidose regime is the need for constant monitoring of glucose level and the need for giving multiple injections per day.

With twice daily regime the child has to run behind the insulin, whereas in multiple daily dosing the insulin runs behind the child.

Majority of the European countries have since then, joined the bandwagon of multi dose regime, and have demonstrated fall in HbA1C and hence reduced number of complications. This has also lead to increased quality of life. Most of the European countries have been able to achieve the target HbA1C of around 7.5.

UK has not been able to switch over to multi dose regime from twice a day. There are multiple causes for this, and lack of resources being the main cause. The uptake of multidose regime has been patchy throughout the UK.

Parents and education of parents regarding the need of multidose regime is a key factor in achieving successful implementation of multi-dose regime.

In our own trust, we have a shifted from the traditional twice a day approach to multidose regime. Over the last 18 months, overwhelming majority of our patients have been shifted to this regime( 46 out of 58). In the remainder, we have not been successful, owing wide range of causes, one of the main being patient choice.

The average HbA1C of children on multi dose regime was 8.2 while that on twice a day was 9.6.

3 of those 12 children have shown at least one complication- including; hyper cholestrenemia and microalbuminuria in 3, Diabetic retinopathy changes in 2 and necrobiosis lipodica in one child.

Diabetes