Diabetes melitus 2

Diabetes mellitus

The contents of this lecture:
• Definition
• Types
• Aetiology
• Pathology and pathophysiology
• Clinical presentations
• Diagnosis
• Treatment
• complications

Diabetes Mellitus

Introduction and Classification

Diabetes mellitus (DM) is a common, chronic, metabolic syndrome characterized by hyperglycemia as a cardinal biochemical feature.

DM is not a single entity but rather a heterogeneous group of disorders.

Three major forms of diabetes and several forms of carbohydrate intolerance are identified.


Aetiologic Classifications of Diabetes Mellitus
Type I diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
Immune mediated, Idiopathic
Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)
Dominant, type 2 due to sulfonylurea receptor 1 mutation.
Other specific types
Genetic defects of β-cell function
Chromosome 20, HNF-4α (MODY1)
Chromosome 7, glucokinase (MODY2)
Chromosome 12, HNF-1α (MODY3)
Insulin promotor factor–1 (MODY4)
HNF-1β (MODY5)
NEUROD1 (MODY6)
Genetic defects in insulin action
Type A insulin resistance, Lipoatrophic diabetes

Diseases of the exocrine pancreas

Pancreatitis, Trauma, pancreatectomy, Neoplasia, Cystic fibrosis , Hemochromatosis

Endocrinopathies

Acromegaly, Cushing disease, Pheochromocytoma, Hyperthyroidism


Drug-or chemical-induced
Pentamidine, Nicotinic acid, Glucocorticoids, Thyroid hormone, Diazoxide, β-Adrenergic agonists, Thiazides,
β-Interferon, cyclosporine

Infections
Congenital rubella, Cytomegalovirus

Other genetic syndromes sometimes associated with diabetes

Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome , Friedreich ataxia Huntington chorea, Laurence-Moon-Biedl syndrome,, and Prader-Willi syndrome

Gestational diabetes mellitus

Neonatal diabetes mellitus
Transient—without recurrence
Transient—recurrence 7–20 yr later
Permanent from onset

TYPE 1 DIABETES MELLITUS (Immune Mediated)

Previously called insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes.
T1DM is the most common endocrine-metabolic disorder of childhood and adolescence, with important consequences for physical and emotional development
T1DM is characterized by low or absent levels of endogenously produced insulin and dependence on exogenous insulin to prevent development of ketoacidosis, an acute life-threatening complication of T1DM.
The natural history includes 4 distinct stages:
(1) Preclinical β-cell autoimmunity with progressive defect of insulin secretion,
(2) Onset of clinical diabetes,
(3) Transient remission “honeymoon period,”
(4) Established diabetes associated with acute and chronic complications and decreased life expectancy.


EPIDEMIOLOGY:

The incidence of T1DM is rapidly increasing in specific regions and shows a trend toward earlier age of onset.
sex & socioeconomic status
Girls and boys are almost equally affected; there is no apparent correlation with socioeconomic status.
Age at onset:
Peaks of presentation occur in 2 age groups:
The 1st peak (at 5–7 years of age) may correspond to the time of increased exposure to infectious agents coincident with the beginning of school;
the 2nd peak (at the time of puberty) may correspond to the pubertal growth spurt induced by gonadal steroids and the increased pubertal growth hormone secretion (which antagonize insulin).
A growing number of cases are presenting between 1 and 2 years of age.

Genetic basis:

The genetics of T1DM cannot be classified according to a specific model of inheritance.
Inheritance of HLA-DR3 or -DR4 antigens appears to confer a 2- to 3-fold increased risk for the development of T1DM.
When both DR3 and DR4 are inherited, the relative risk for the development of diabetes is increased by 7- to 10-fold.
Inheritance of HLA-DR2 appear to be protective against diabetes.
The concordance rate among identical twins is only 30–50%, suggesting either the participation of environmental triggering factors or other genetic factors
The risk to offspring of a diabetic parent is 2–5%, with the higher risk occurring in the offspring of a diabetic father.
Environmental basis:
No dominant environmental agent responsible for triggering T1DM Environmental risk determinants can be classified as :
Viral infections:
coxsackie B3, coxsackie B4, cytomegalovirus, rubella, and mumps can infect human β cells.
Only congenital rubella infection is associated with diabetes in later life (10–12%)


Seasonal association:
Seasonal variations occur in the incidence of T1DM with greater frequency in autumn and winter months
Puberty:
pubertal changes may contribute to accelerated onset of T1DM. The pubertal peak in onset of type 1 DM occurs earlier in girls than boys.
Dietary factors:
Dietary factors have been implicated in the pathogenesis of T1DM, but the role of dietary factors in induction of islet autoimmunity remains controversial.
cow's milk & initial exposure of infants to cereals before 4 months of age has been suggested to increase the risk of islet cell autoimmunity

Body mas index:

There may be a greater risk of T1DM among individuals who were heavier as young children.
Insulin resistance is a function of fat mass, Therefore, limiting excessive weight gain may be as important for children susceptible to T1DM as for those at genetic risk for T2DM.

Chemicals & drugs:

Drugs such as alloxan, streptozotocin (STZ), and pentamidine are directly cytotoxic to β cells and cause diabetes in experimental animals and humans.

Psychosocial stress

may constitute a trigger mechanism for T1DM or the autoimmune process behind the disease.
(uncover latent cases of DM)

PATHOGENESIS

Autoimmune Injury:

T1DM is a chronic, T cell–mediated autoimmune disease that results in the destruction of the pancreatic islets.
Genetic predisposition and environmental factors lead to initiation of an autoimmune process against the pancreatic islets which leads to a gradual and progressive destruction of β cells, with loss of insulin secretion.

* at the onset of clinical diabetes, 80–90% of the pancreatic islets are destroyed. Regeneration of new islets has been detected at onset of T1DM, and it is thought to be responsible for the honeymoon phase (a transient decrease in insulin requirement associated with improved β-cell function).


* In young diabetic children, especially those of DR3/DR4 haplotypes, the destruction of β cells is almost complete during the 1st 3 yr after the onset of hyperglycemia, whereas in older patients complete β-cell destruction may take up to 10 yr.

*most individuals progressing to overt diabetes express multiple anti–islet cell antibodies (GAD65, ICA512/IA-2, and IAA) before the onset of diabetes.

PATHOPHYSIOLOGY

In normal metabolism, there are regular swings between the postprandial, high-insulin anabolic state and the fasted, low-insulin catabolic state that affect liver, muscle, and adipose tissue .

T1DM is a progressive low-insulin catabolic state in which feeding does not reverse but rather exaggerates these catabolic processes.

With moderate insulinopenia, glucose utilization by muscle and fat decreases and postprandial hyperglycemia appears.
At even lower insulin levels, the liver produces excessive glucose via glycogenolysis and gluconeogenesis, and fasting hyperglycemia begins.


Hyperglycemia produces an osmotic diuresis (glycosuria) when the renal threshold is exceeded (180 mg/dL;= 10 mmol/L).

The resulting loss of calories and electrolytes, as well as the persistent dehydration, produce a physiologic stress with hypersecretion of stress hormones (epinephrine, cortisol, growth hormone, and glucagon).

These hormones, in turn, contribute to the metabolic decompensation:

by further impairing insulin secretion (epinephrine),

by antagonizing insulin action (epinephrine, cortisol, GH),

by promoting glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis (glucagon, epinephrine, growth hormone, and cortisol)

by decreasing glucose utilization and glucose clearance (epinephrine, growth hormone, cortisol).

The combination of insulin deficiency and elevated plasma values of the counter-regulatory hormones is also responsible for accelerated lipolysis and impaired lipid synthesis, with resulting increased plasma concentrations of total lipids, cholesterol, triglycerides, and free fatty acids.

The hormonal interplay of insulin deficiency and glucagon excess shunts the free fatty acids into ketone body formation; the rate of formation of these ketone bodies, principally β-hydroxybutyrate and acetoacetate, exceeds the capacity for peripheral utilization and renal excretion.

Accumulation of these keto acids results in metabolic acidosis (diabetic ketoacidosis, DKA) and compensatory rapid deep breathing in an attempt to excrete excess CO2 (Kussmaul respiration).
Acetone, formed by nonenzymatic conversion of acetoacetate, is responsible for the characteristic fruity odor of the breath.


Ketones are excreted in the urine in association with cations and thus further increase losses of water and electrolyte.

With progressive dehydration, acidosis, hyperosmolality, and diminished cerebral oxygen utilization, consciousness becomes impaired, and the patient ultimately becomes comatose.

Insulin S.glucose glucosuria polyuria

IC glucose thirst

Adrenaline,nor adrenaline dehydration

GH, cortisol, glucagon

Lipolysis Wt loss Kussmaul respiration

Ketone bodies ketoacidosis

ketonuria
coma

• Clinical presentations:

• Classical presentation: (60-80%) polyuria, polydipsia, polyphagia and Wt. loss.


• Diabetic ketoacidosis (DKA): (20–40%)
abdominal discomfort, nausea, vomiting, sever dehydration with persistent polyuria (the degree of dehydration may be clinically underestimated because intravascular volume is conserved at the expense of intracellular volume).
• Ketoacidosis exacerbates prior symptoms & leads to Kussmaul respirations (deep, heavy, rapid breathing), fruity breath odor (acetone), diminished neurocognitive function, and possible coma.
• Others : candidal vaginitis, secondary enuresis.

This entire progression happens much more quickly (over a few weeks) in younger children.

In infants, most of the weight loss is acute water loss and there will be an increased incidence of DKA at diagnosis.

In adolescents, the course is usually more prolonged (over months), and most of the weight loss represents fat loss due to prolonged starvation. Additional weight loss due to acute dehydration may occur just before diagnosis.

In any child, the progression of symptoms may be accelerated by the stress of an intercurrent illness or trauma, when counter-regulatory (stress) hormones secretion increased.

DIAGNOSIS

The diagnosis of T1DM is usually easy.

Although most symptoms are nonspecific, the most important clue is an inappropriate polyuria in any child with dehydration.

Hyperglycemia, glycosuria, and ketonuria can be determined quickly.

In the obese child, T2DM must be considered.


DIABETES MELLITUS (DM)

Symptoms of DM plus Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L)

or
Symptoms of DM plus random plasma glucose ≥200 mg/dL (11.1 mmol/L)
Or
2-hr plasma glucose during the OGTT ≥200 mg/dL

IMPAIRED GLUCOSE TOLERANCE (IGT)

Fasting glucose: 110–125 mg/dL (6.1–7.0 mmol/L)

2-hr plasma glucose during the OGTT: ≥ 140 mg/dL<200 mg/dL (11.1 mmol/L)

Once hyperglycemia is confirmed, it is important to determine whether DKA is present (presence of ketonuria, an increased ion gap, a decreased serum bicarbonate (or total CO2) and pH, and an elevated effective serum osmolality, indicating hypertonic dehydration.
and to evaluate electrolyte abnormalities—even if signs of dehydration are minimal.

A baseline hemoglobin A1C (HbA1c) allows an estimate of the duration of hyperglycemia and provides an initial value by which to compare the effectiveness of subsequent therapy.

In the obese child, testing for autoimmunity to β cells is necessary ( because the possibility of T2DM) but it is not necessary in thin diabetic patients.


Other autoimmunities associated with type 1 diabetes should be checked for including:
celiac disease (by tissue transglutaminase IgA and total IgA)

thyroiditis (by antithyroid peroxidase and antithyroglobulin antibodies).

Because significant physiologic distress can disrupt the pituitary-thyroid axis, free thyroxine (T4) and TSH levels should be checked after the child is stable for a few weeks.

• SEVERE

• MODERATE
• MILD
• NORMAL
• Less than 10
• 10-15
• 16-20
• 20-28
• CO2 (mEq/L, venous)
• Less than 7.15
• 7.15-7.25
• 7.25-7.35
• 7.35-7.45
• PH (venous)
• Kussmaul or depressed respirations; sleepy to depressed sensorium ,coma
• Kussmaul respirations; oriented but sleepy; arousable
• Oriented, alert but fatigued
• No change
• clinical
DKA may be classified as mild, moderate, or severe (Table below), and the range of symptoms depends on the depth of ketoacidosis.


TREATMENT

Therapy depends on the degree of insulinopenia at presentation.

Most children with new diabetes (60–80%) have mild to moderate symptoms, have minimal dehydration with no history of emesis, and have not progressed to ketoacidosis.
( ie: classical presentation or non ketotic onset)

Once DKA has resolved in the newly diagnosed child, therapy is transitioned to that described for children with non ketotic onset.

Children with previously diagnosed diabetes who develop DKA are usually transitioned to their previous insulin regimen.

New-Onset Diabetes Without Ketoacidosis.

Excellent diabetes control involves many goals:
1.to maintain a balance between tight glucose control and avoiding hypoglycemia,
2.to eliminate polyuria and nocturia,
3.to prevent ketoacidosis,
4.to permit normal growth and development with minimal effect on lifestyle.

Insulin Therapy

Children with long-standing diabetes and no insulin reserve require about:
0.7 U/kg/d if pre pubertal,
1.0 U/kg/d at mid puberty,
1.2 U/kg/d by the end of puberty.
A reasonable dose in the newly diagnosed child, then, is about 60–70% of the full replacement dose based on pubertal status.


The optimal insulin dose can only be determined empirically, with frequent self-monitored blood glucose levels and insulin adjustment by the diabetes team.
Residual β-cell function usually fades within a few months and is reflected as a steady increase in insulin requirements.

Types of insulin and their regimens used are:

Actrapid (soluble) , monotard (lente), & mixtard.

• Two doses regimen ( actrapid 1/3 and monotard 2/3) or mixtard only with 2/3 of the daily dose in the morning and 1/3 in the evening,
( sometimes we personalize the dose and the % of the combination).
However, such a schedule would provide poor coverage for lunch and early morning, and would increase the risk of hypoglycemia at midmorning and early night.

2. Basal bolus regimen

insulin analogs (Lispro (L) and aspart) which are absorbed much quicker because they do not form hexamers. their action started within 10 minutes with duration of action of 2 hours without peak.
The long-acting analog glargine (G) creates a much flatter 24-hr profile, making it easier to predict the combined effect of a rapid bolus (L or A) on top of the basal insulin, producing a more physiologic pattern of insulin effect.

The basal insulin glargine should be 25–30% of the total dose in toddlers and 40–50% in older children.
The remaining portion of the total daily dose is divided evenly as bolus injections for the 3 meals .

Postprandial glucose elevations are better controlled, and between-meal and night time hypoglycemia are reduced.


Frequent blood glucose monitoring and insulin adjustment are necessary in the 1st weeks as the child returns to routine activities and adapts to a new nutritional schedule, and as the total daily insulin requirements are determined.
Insulin Pump Therapy
Inhaled Insulin
Pre prandial inhaled insulin is being evaluated in adults with T1DM and T2DM.
Pre-meal oral insulin (Oralin) has been evaluated in comparison with oral hypoglycemic agents, mostly in patients with T2DM. The clinical data appear promising, but further evaluation of efficacy in T1DM is needed


Ketoacidosis
Reversal of DKA is associated with inherent risks that include hypoglycemia, hypokalemia, and cerebral edema.
Any protocol must be used with caution and close monitoring of the patient
Hyperglycemia and Dehydration:
Insulin (0.1 unit/ kg/ hour) IV or IM must be given at the beginning of therapy to accelerate movement of glucose into cells, to stop hepatic glucose production, and to halt the movement of fatty acids from the periphery to the liver.
Rehydration also lowers glucose levels by improving renal perfusion and enhancing renal excretion.
The combination of these therapies usually causes a rapid initial decline in serum glucose levels.
Once glucose goes below 180 mg/dL (10 mmol/L), the osmotic diuresis stops and rehydration accelerates without further increase in the infusion rate.

Repair of hyperglycemia occurs well before correction of acidosis. Therefore, insulin is still needed to control fatty acid release after normal glucose levels are reached.

To continue the insulin infusion without causing hypoglycemia, glucose must be added to the infusion, usually as 5% or 1/5 GS solution.

Glucose should be added when the serum glucose has decreased to about 250 mg/dL (14 mmol/L) so that there is sufficient time to adjust the infusion before the serum glucose falls further.

The insulin infusion can also be lowered from the initial maximal rate once hyperglycemia has resolved.

During repair of fluid deficits we must take in consideration the potential risk of cerebral edema.
All fluid intake and output should be closely monitored.

*Limited ice chips may be given as a minimal oral intake.

*Although patients with DKA have a total body potassium deficit, the initial serum level is often normal or elevated.
This is due to the movement of potassium from the intracellular space to the serum, both as part of the ketoacid buffering process and as part of the catabolic shift.


*Mildly elevated creatinine or BUN is not a reason to withhold potassium therapy if good urinary output is present.

Keto Acid Accumulation:

Low insulin infusion rates (0.02–0.05 units/kg/h) are usually sufficient to stop peripheral release of fatty acids, thereby eliminate the production of ketone bodies

Bicarbonate buffers, regenerated by the distal renal tubule and by metabolism of ketone bodies, and their excretion in the urine steadily repair the acidosis once ketoacid production is controlled.

Bicarbonate therapy is rarely necessary and may even increase the risk of hypokalemia and cerebral edema.
(only indicated in case of sever acidosis , ie :when the blood PH < 7.1)
Persistent acidosis may indicate inadequate insulin or fluid therapy, infection, or rarely lactic acidosis.

Urine ketones may be positive long after ketoacidosis has resolved , Therefore, persistent ketonuria may not accurately reflect the degree of clinical improvement and should not be relied upon as an indicator of therapeutic failure.

Cerebral edema:

For all but the mildest cases, frequent neurologic checks for any signs of increasing intracranial pressure, such as a change of consciousness, depressed respiration, worsening headache, bradycardia, apnea, pupillary changes, papilledema, posturing, and seizures.
Mannitol 10% (10gm /100ml) must be readily available for use at the earliest sign of cerebral edema.
All patients with DKA should be checked for initiating events in order to avoid them to prevent the recurrence of DKA.

Management of DKA

• Admission to the emergency unit.
• ABC if the patient is comatosed and O2 to be delivered via mask.
• IV LINE and Aspiration of blood for RBS, B.urea, S.Cr, S.K, S.Na, S.Cl, CBP, B.C/S ,ASTRUP
• Urine for ketone, sugar, pus cell.
• Calculation of the deficit and maintenance of the fluids ; to be replaced over 36- 48 hours (hyperosmotic dehydration)
• Oral fluid is stopped and only sucking of chips of ice is allowed .
• IV fluid (0.9%N/S or RL bolus 10 - 20ml / kg /1st hour) and then rate of fluid replacement from the 2nd hour till resolution of DKA calculated according to the following formula :
• ( 85× Bwt + maintenance – bolus / 23 hours= rate / hour ).
• Change the type of the fluid from N/S to G/S (1/2, 1/3,1/5) when RBS is less than 250 mg/dl . WHY?


• 6 KCl: the patient is hypokalemic even if S.K was normal .WHY?
• 20 - 40 meq/L (1 ml = 2 meq) and sometimes increased to 60 meq/L .
• 7. INSULIN : either IV continuous infusion via a separate IV line started at time zero OR interrupted IM or IV dose started after one hour (the dose in both ways is 0.1 unit /kg/h)
• Changed to SC insulin and start oral fluid when there are no emesis, or acidosis with normal electrolytes. HOW ?
• 8. Sod. Bicarbonate : only used in sever acidosis (PH less than 7.1) in a dose of 20-40 meq ( 1 ml = 1 meq) with the fluid. WHY?

• 9. Mannitol :10% if signs of cerebral oedema appear in a dose of 1 gm / kg IV infusion.
• 10. Antibiotic : if infection is present.
• checking for the initiating events should be done and treated & avoid to be repeated
*NB: put 50 unit of soluble (actrapid) insulin in one pint (500 cc) NS = 0.1 u/cc & use EVAC to control the rate of infusion OR
use micro-drip (burette) & put 10 unit of soluble insulin for every 100 cc NS.
In either ways you must flush 1cc/ Kg rapidly to saturate the insulin receptors & then the rate will be:
1CC /Kg /hour = 60 micro drops /kg /hr
= one micro drop /kg/min.
The rate should be reduced to 1/2 if RBS is below 150 mg/dl

• NEVER FORGET THE FLOW SHEET FOR DIABETIC KETOACIDOSIS

• (name, age, date, time, BWt & SA, PR, BP,PH, RBS , S.electrolyte, Fluid input, output, insulin dose, signs of cerebral oedema, and notes).

Basic Education

Therapy consists not only of initiation and adjustment of insulin dose but also of education of the patient and family.
In the acute phase, the family must learn the “basics,” which includes:
*monitoring the child's blood glucose and urine ketones,
*preparing and injecting the correct insulin dose subcutaneously at the proper time,
*recognizing and treating low blood glucose reactions, and
*having a basic meal plan.


Most families are trying to adjust psychologically to the new diagnosis of diabetes in their child and thus have a limited ability to retain new information.
Written materials covering these basic topics help the family during the 1st few days.

Nutritional Management

Nutrition plays an essential role in the management of patients with T1DM. This is of critical importance during childhood and adolescence, when appropriate dietary intake is required to meet the needs for energy, growth, and pubertal development.
The caloric mixture should comprise approximately
55% carbohydrate, 30% fat, and 15% protein.
Approximately 70% of the carbohydrate content should be derived from complex carbohydrates such as starch;
intake of sucrose and highly refined sugars should be limited.

Carbohydrate counting has become a mainstay in the nutrition education and management of patients with DM.
Each carbohydrate exchange unit is 15 g.
Patients and their families are provided with information regarding the carbohydrate contents of different foods and food label reading.
The total daily caloric intake is divided to provide 20% at breakfast, 20% at lunch, and 30% at dinner, leaving 10% for each of the midmorning, midafternoon, and evening snacks, if they are desired.
Emphasis should be placed on regularity of food intake and on constancy of carbohydrate intake.

Monitoring

Success in the daily management of the diabetic child can be measured by the ability of the family, and subsequently the child, in assuming responsibility for daily “diabetic care.”
Monitoring often include : insulin dose, unusual physical activity, dietary changes, hypoglycemia, intercurrent illness, and other items that may influence the blood glucose.
Self-monitoring of blood glucose (SMBG) is an essential component of managing diabetes. Accu check devices to measure the B. glucose within one minute.
Parents and patients should be taught to use these devices and measure blood glucose at least 4 times daily—before breakfast, lunch, and supper and at bedtime, and records the results and other notes in special notebook to be reviewed with doctor during follow up visit.
Ideally, the blood glucose concentration should range from approximately 80 mg/dL in the fasting state to 140 mg/dL after meals.



Ideally, the blood glucose concentration should range from approximately 80 mg/dL in the fasting state to 140 mg/dL after meals.
A reliable index of long-term glycemic control is provided by measurement of glycosylated hemoglobin.
HbA1C represents the fraction of hemoglobin to which glucose has been non enzymatically attached in the bloodstream.
HbA1C measurement reflects the average blood glucose concentration from the preceding 2–3 mo.
It is recommended that HbA1C measurements be obtained 3 to 4 times per year to obtain a profile of long-term glycemic control.
the HbA1C fraction:
in nondiabetic individuals, is usually less than 6%.
in diabetics:
values of 6–7.9% represent good metabolic control,
values of 8.0–9.9%, fair control,
values of 10.0% or higher, poor control.

Exercise:

No form of exercise, including competitive sports, should be forbidden to the diabetic child. A major complication of exercise in diabetic patients is the presence of a hypoglycemic reaction during or within hours after exercise.
glucoregulation is likely to be improved through the increased utilization of glucose by muscles.
The major contributing factor to hypoglycemia with exercise is an increased rate of absorption of insulin from its injection site.
Regular exercise also improves glucoregulation by increasing insulin receptor number.
In patients who are in poor metabolic control, vigorous exercise may precipitate ketoacidosis because of the exercise-induced increase in the counter-regulatory hormones.
In anticipation of vigorous exercise, one additional carbohydrate exchange may be taken before exercise, or the total dose of insulin may be reduced by about 10–15% on the day of the scheduled exercise.
It is also important to watch for delayed hypoglycemia several hours after exercise.


Management During Infections
Although infections are no more common in diabetic children than in nondiabetic ones, they can often disrupt glucose control and may precipitate DKA.
In addition, the diabetic child is at increased risk of dehydration if hyperglycemia causes an osmotic diuresis or if ketosis causes emesis.
Counter-regulatory hormones associated with stress blunt insulin action and elevate glucose levels.
If anorexia occurs, however, lack of caloric intake increases the risk of hypoglycemia.
Although children younger than 3 year tend to become hypoglycemic and older children tend toward hyperglycemia, the overall effect is unpredictable.
Therefore, frequent blood glucose monitoring and adjustment of insulin doses are essential elements of sick day guidelines.
One regimen is to add 10 -20% of the total dialy dose as actrapid before each meal in addition to the usual daily dose if hyperglycemia developed
( two doses daily regimen).
The overall goals are to maintain hydration, control glucose levels, and avoid ketoacidosis.

complications of the management:

*Hypoglycemic Reactions:
Hypoglycemia is the major limitation to tight control of glucose levels.
Most children with T1DM can expect mild hypoglycemia each week, moderate hypoglycemia a few times each year, and severe hypoglycemia every few years.

These episodes are usually not predictable, although exercise, delayed meals or snacks, wrong dose and wide swings in glucose levels increase the risk.

Hypoglycemia can occur at any time of day or night.

• Early symptoms and signs (mild hypoglycemia) may occur with a sudden decrease in blood glucose to levels that do not meet standard criteria for hypoglycemia in non diabetic children.
• The child may show pallor, sweating, apprehension , hunger, tremor, and tachycardia, all due to the surge in catecholamines as the body attempts to counter the excessive insulin effect.
• Behavioral changes such as tearfulness, irritability, and aggression are more prevalent in children.
• As glucose levels decline further, cerebral glucopenia occurs with drowsiness, personality changes, mental confusion, and impaired judgment (moderate hypoglycemia),
progressing to inability to seek help and seizures or coma (severe hypoglycemia).


Prolonged severe hypoglycemia can result in a depressed sensorium or stroke-like focal motor deficits that persist after the hypoglycemia has resolved.

Although permanent squeale are rare, severe hypoglycemia is frightening for the child and family and can result in significant reluctance to attempt even moderate glycemic control afterward.

Important counter-regulatory hormones in children include growth hormone, cortisol, epinephrine, and glucagon. The latter two seem more critical in the older child.

Many older patients with long-standing T1DM lose their ability to secrete glucagon in response to hypoglycemia.

In the young adult, epinephrine deficiency may also develop as part of a general autonomic neuropathy

This substantially increases the risk of hypoglycemia because the early warning signals of a declining glucose level are due to catecholamine release.

Recurrent hypoglycemic episodes associated with tight metabolic control may aggravate partial counter-regulatory deficiencies, producing a syndrome of hypoglycemia unawareness and reduced ability to restore euglycemia (hypoglycemia-associated autonomic failure).

Avoidance of hypoglycemia allows some recovery from this unawareness syndrome.

The most important factors in the management of hypoglycemia are:

*an understanding by the patient and family of the symptoms and signs of the reaction and an anticipation of known precipitating factors such as sports activities. Tighter glucose control increases the risk.

*A source of emergency glucose should be available at all times and places, including at school and during visits to friends.

*If possible, it is initially important to document the hypoglycemia before treating, because some symptoms may not always be due to hypoglycemia.

*Any child suspected of having a moderate to severe hypoglycemic episode should be treated before testing.


• *It is important not to give too much glucose;
• 5–10 g should be given as juice or a sugar-containing carbonated beverage or candy and the blood glucose checked 15–20 minutes later.
• *Patients, parents, and teachers should also be instructed in the administration of glucagon when the child cannot take glucose orally.
• An injection kit should be kept at home and school.
• The intramuscular dose is 0.5 mg if the child weighs less than 20 kg and 1.0 mg if more than 20 kg.
• This produces a brief release of glucose from the liver.
• Parents must then be prepared to take the child to the hospital for IV glucose administration, if necessary.

*Somogyi Phenomenon, Dawn Phenomenon, and Brittle Diabetes:

blood glucose levels increase in the early morning hours before breakfast.
The dawn phenomenon is thought to be due mainly to overnight growth hormone secretion and increased insulin clearance.
It is a normal physiologic process seen in most non diabetic adolescents, who compensate with more insulin output.
A child with T1DM cannot compensate so we need to increase the evening lente insulin.
the Somogyi phenomenon, a theoretical rebound from late night or early morning hypoglycemia, thought to be due to an exaggerated counter-regulatory response.
so we need to decrease the evening insulin dose.
Continuous glucose monitoring systems may help clarify the cause of the elevated morning glucose levels.
The term brittle diabetes has been used to describe the child, usually an adolescent female, with unexplained wide fluctuations in blood glucose, often with recurrent DKA, who is taking large doses of insulin (no physiological abnormality but usually psychological cause)

*NONADHERENCE:

Family conflict, denial, and feelings of anxiety find expression in non adherence to instructions regarding nutritional and insulin therapy and in noncompliance with self-monitoring
*FEAR OF SELF-INJECTING AND SELF-TESTING:
Extreme fear of self-injecting insulin (injection phobia) is likely to compromise glycemic control as well as emotional well-being.
Children and adolescents may either omit insulin dosing or refuse to rotate their injection sites because repeated injection in the same site is associated with less pain sensation.
Failure to rotate injection sites results in subcutaneous scar formation (lipohypertrophy).
Insulin injection into the lipohypertrophic skin is usually associated with poor insulin absorption and/or insulin leakage with resultant suboptimal glycemic control.


LONG-TERM COMPLICATIONS:
The increasingly prolonged survival of the diabetic child is associated with an increasing prevalence of complications.
Limited joint mobility (LJM) (prayer sign) : highly correlated with micro vascular complication of DM and can be used as rapid screening test in outpatient clinic.
Complications of DM can be divided into 3 major categories—
(1) microvascular complications, specifically, retinopathy and nephropathy;
(2) macrovascular complications, particularly accelerated coronary artery disease, cerebrovascular disease, and peripheral vascular disease;
(3) neuropathies, both peripheral and autonomic, affecting a variety of organs and systems.
In addition, cataract may occur more frequently.

• PREDICTION AND PREVENTION

• There is currently no known agent capable of preventing T1DM.
• There are several obstacles to finding prevention strategy. These include
• ethical issues surrounding prediction,
• treatment dilemma,
• selection of populations at risk and treatment strategies, and
• (4) finding new preventive agents.