diabetes mellitus agnieszka krosnowska - … · diabetes mellitus it is a group of metabolic...

DIABETES MELLITUS

Agnieszka Krosnowska

DIABETES MELLITUS

● It is a group of metabolic disease in which there are high blood sugar level over a prolongated period.

● It is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced.

DIABETES MELLITUS- diagnosis

● Two fasting plasma glucose level >= 7,0 mmol/l (126 mg/dl)

● Plasma glucose >= 11,1 mmol/l (200mg/dl) two hours after a max. 75 g ( 1,75 g/kg) glucose load as in a glucose tolerance test.

● Symptoms of high blood sugar (polyuria, polidipsia and weight loss) and casual plasma glucose >= 11,1 mmol/l (200mg/dl).

● Glycate hemoglobin (HbA1c)>= 48 mmol/mol (>= 6,5 DCCT%)- not specific one.

● IMPAIRED FASTING GLUCOSEpeople with fasting glucose levels from 5,6 to 6,9 mmol/l (100-125 mg/dl)

● IMPAIRED GLUCOSE TOLERANCEpeople with plasma glucose at or above 7,8 mmol/l (140mg/dl), but not over 11,1 mmol/l (200mg/dl), two hours after a oral glucose load

DIABETES MELLITUS

● TYPE 1 The most common type occurring in childhood, which is caused by autoimmune destruction of the insulin- producing beta cells (islets) of the pancreas. Patients with DM1 have permanent insulin deficiency and require insulin.

● TYPE 2 INSULIN RESISTANCE followed later by beta-cell failure

DM2 is less common in children and results from insulin resistance and relative insulin deficiency, usually with obesity individuals with DM2 are not dependent on insulin for survival, but they may require insulin to achieve adequate glycemic control.

TYPE 3. OTHER SPECIFIC TYPES● MODY = maturity-onset diabetes of the younge- is an AD

inherited form of diabetes, due to one of the several single-gene mutations, causing defects in insulin production. People with MODY often can control it without using insulin.

● Infections e.g congenital rubella● Drugs e.g corticosteroids, tacrolimus, L-asparaginase● Cyctis fibrosis, hemochromatosis (diabetes dronze) - secondary

one● Cushing syndrome● Genetic/chromosomal syndromes e.g Down and Turner● Mitochondrial diabetes- associated with deafness and other

neurological defects, maternal transmission-mtDNA point mutation.

● Neonatal diabetes-transient neonatal- immediately after birth- last 1-3 months

-permanent neonatal- other panceratic disease possible. It can be treated with sulfonylourea-derivatives like glimepiride

TYPE 4. GESTATIONAL DIABETES GDMAbnormal glucose tolerance only during pregnancy, which reverts to normal post partum, increase risk for late onset of diabetes.

LADA- Latent autoimmune diabetes of adults.It is a condition in which type 1 DM develops in adults.

PREDIABETESIndicates a condition that occures when a person's blood glucose levels are higher than normal, not high enough for diagnosis of type 2 DM.

● DM1 is the most common pediatric endocrine disorder and affects approximatly 1 in 300-500 children younger than 18 years old.

● 30: 100 000 children in Scandynavian children population● 1: 100 000 children in Japan children population

● Both genetic and environmental precipitants play a role in DM1

● Multiple genetic loci in the major histocompatability (HLA) region predispose to the development of DM1- DR 3/4, 4/4, DQ 0201/0302, 0300/0302.

● The environmental triggers include infectious agent (coxsackie B, rubella virus- molecular mimicry), components of the diet (early exposure to cow milk in whose who has a genetic risk), and toxins.

● An identical twin of diabetic have an 30-50% chance of developing the disease.

● First- degree relatives of DM1 patients have 15-fold dicreased risk of developing diabetes in comparison to general population.

● However, approximately 85% of all patients develop DM1 does not have an affected family member.

● A risk of child developing diabestes if a parent has DM1 is increase (1 in 20-40 if the father is affected, 1 in 40-80 if it is the mother).

● Beta- cell mass is destoyed gradually over the time in genetically susceptible individuals after exposure to environmental triggers that induce T-cell-mediated beta-cell injury and producion of humoral autoantibodies.

● -Anti-GAD- Anti Glutamic Acid Decarboxylase Autoantibodies-ICA- Islet Cell Cytoplasmic Autoantibodies -IAA- Insulin Autoantibodies-IA-A2 – Autoantibodies against a member of the transmembrane tyrosine phosphatase family, Insulinoma- Associated Antigen-2 (IA-2)- Zn T8Ab- Zinc Transporter 8

CLINICAL FEATURES

● There are two peaks of presentation of DM1: preschool and teenagers.

● It is uncommon before the age of 1 year, but the incidence rises steadily during the early school years to peak at 12-13 years of age.

● Most children are diagnosed after few weeks history of the symptoms.

● If the clinical features of DM 1 are not detected early- diabetic ketoacidosis can occure (< 10%)

SYMPTOMS AND SIGNS OF DIABETES 1

● most common – the classical triad-polydipsia-polyuria-weight loss

● less common-enuresis-skin sepsis-candida and other infections

DIABETIC KETOACIDOSIS

Can occur during periods of intercurrent illness when greater insulin requirements go unmet in the presence of elevated

concentration of the conterregulatory hormones

Can occur if the clinical features of DM1 are not detected early.

Can occur in patients with known diabetes if insulin injections are omitted.


● DKA usually occures as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulator hormones- glucagon, cortisol, grow hormone, epinephrine. This type of hormonal imbalances enhances hepatic gluconeogenesis, glycogenolysis (result in severe hyperglycemia) and lipolysis (increases serum free fatty acids).

● Hepatic metabolism of free fatty acids as an alternative energy source (ie, ketogenesis) results in accumulation of acidic intermediate and end metabolites (ie, ketones, ketoacids). Ketone bodies have generally included acetone, beta-hydroxybutyrate, and acetoacetate.


● Meanwhile, increased proteolysis and decreased protein synthesis as result of insulin deficiency add more gluconeogenic substrates to the gluconeogenesis process.

● In addition, the decreased glucose uptake by peripheral tissues due to insulin deficiencyincreases hyperglycemia.

DIABETIC KETOACIDOSIS● Ketone bodies are produced from acetyl coenzyme A mainly in

the mitochondria within hepatocytes when carbohydrate utilization is impaired because of insulin deficiency, such that energy must be obtained from fatty acid metabolism.

●

● High levels of acetyl coenzyme A present in the cell inhibit the pyruvate dehydrogenase complex, but pyruvate carboxylase is activated. Thus, the oxaloacetate generated enters gluconeogenesis rather than the citric acid cycle, as the latter is also inhibited by the elevated level of nicotinamide adenine dinucleotide (NADH) resulting from excessive beta-oxidation of fatty acids.

● Progressive rise of blood concentration of the acidic organic substances initially leads to a state of ketonemia, although extracellular and intracellular body buffers can limit ketonemia in its early stages.

● When the accumulated ketones exceed the body's capacity to extract them, they overflow into urine (ketonuria). If the situation is not treated promptly, a greater accumulation of organic acids leads to frank clinical metabolic acidosis (ketoacidosis), with a significant drop in pH and bicarbonate serum levels. Respiratory compensation for this acidotic condition results in Kussmaul respirations-rapid, shallow breathing (sigh breathing) that as the acidosis grows more severe, becomes slower, deeper, and labored (air hunger).


● Ketone bodies induce nausea and vomiting that consequently aggravate fluid and electrolyte loss already existing in DKA. Moreover, acetone produces the fruity breath odor that is characteristic of ketotic patients.

● Glycosuria leads to osmotic diuresis, dehydration and hyperosmolarity (impaired renal function).

● Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances. The most characteristic is total body potassium loss, which level in serum may be low, within the reference range, or even high.

● Potassium loss is caused by a shift of potassium from the intracellular to the extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis. Much of the shifted extracellular potassium is lost in urine because of osmotic diuresis

● Patients with initial hypokalemia are considered to have severe and serious total body potassium depletion. High serum osmolarity also drives water from intracellular to extracellular space, causing dilutional hyponatremia. Sodium also is lost in the urine during the osmotic diuresis.

● The combined effects of serum hyperosmolarity, dehydration, and acidosis result in increased osmolarity in brain cells that clinically manifests as changing in the level of consciousness.


1) the arterial pH is less than 7,252) the serum bicarbonate level is less than 15 mEq/L3) ketones are elevated in serum or urine

● Smell of acetone on breth● Vomiting● Dehydration● Abdominal pain, can mimic an acute abdomen ● Kussmaul breathing● Hypovolaemic shock● Drowsiness● Coma and death

DIABETIC KETOACIDOSIS- traetment

● If in shock, an initial i.v. fluid bolus of glucosefree isotonic solution at 10-20 ml/kg should be first given.

● Dehydratation should then be corrected slowly over 36 to 48 hours.

● Rapid dehydratation should be avoided as it may lead do cerebral oedema

● Monitor fluid input and output.


● Calculate children total fluid requirment for the first 48 hours by adding the estimated fliud deficit to the fluid maintance requirement.-5% fluid deficit in mild to moderate DKA ( pH>7,1)-10% fluid deficit in severe DKA (pH<7,1)

● Maintance fluid requirement:-if the weight less than 10kg give 2 ml/kg/hour-if the weight 10-40kg give 1 ml/kg/hour-if the weight more than 40kg give a fixed volume of 40ml/hour

Scale of dehyratation


● First day:-Maintenance fluid requirement for all 24 hours plus 50% of the fluid deficit, calculate at the beginning of the treatment.+first two hours- bolus: 10ml/kg 0,9% NaCl+another two hours- 20% of the whole calculate fluid +another four hours- 20% of the whole calculate fluid+another sixteen hours- the rest one of the calculate fliud

● Second day:-Maintenance fluid requirement for all 24 hours plus the rest 50% of the fluid deficit, calculate at the beginning of the treatment.


● Start intravenous insulin infusion 1-2 hours after begining intravenous fluid therapy.

● Use soluble insulin infusion at a dosage between 0,05-0,1 units/kg/hours.

● Do not give bolus doses of intravenous insulin.● If a child with DKA is using insulin pump therapy,

disconnect the pump when starting intravenous insulin therapy.

● Start subcutaneous insulin (when the acidosis has been corrected and patient tolerates oral feeding) at least 30 minutes before stopping intravenous insulin.


● Change fluids to 0,9% sodium chloride with 5% glucose and 40 mmol/litre potassium chloride once the plasma glucose concenration falls below 14 mmol/l in children with DKA.

● If during treatment for DKA a child plasma glucose falls below 6 mmol/l:-increase the glucose concentration of the intravenous fliud infusion, and-if there is persisting ketosis, continue to give insulin at a dosage at least 0,05 units/kg/hours

● Although a metabolic acidosis is present, bicarbonate should be avoided. The acidosis will self-correct with fluid and insulin therapy. Potential adverse effects of bicarbonate administration include paradoxal increase in CNS acidosis, potential tissue hypoxia, abrupt osmotic changes and increased risk of development of cerebral oedema.


● Regardless of the serum potassium concentration atpresentation, total body potassium depletion is likely.

● It will fall following treatment with insulin and rehydratation (potassium is exchanged for intracellular hydrogen ions). ● Potassium replacement therapy should be started

immediately if the patient is hypokalaemic, but should overwise be started when insulin therapy is begun.

● K< 3 mmol/l → 0,5 mmol/kg/hour KClK 3-4 mmol/l → 0,4 mmol/kg/hour KClK 4-5 mmol/l → 0,3 mmol/kg/hour KClK 5-6 mmol/l → 0,2 mmol/kg/hour KClK > 6 mmol/l → It should not be added to IV fluids

● Hipokalemia

● Serum sodium is an unreliable measure of the degree of ECF concentration due to the diulational effect of the hyperglucaemia and fluid shift from ICF to the ECF

● Corrected sodium: messured Na + {(glucose- 5,5)- 5,5} mmol/l

● As the plasma glucose concentration falls, measured and corrected sodium should rise steadily.

● A fall in serrum sodium and osmolality of > 3 mOsm/kg/hour are ones of the few biochemical correlates of impending cerebral oedema.

● Effective osmolality:2x (Na uncorrected + K) + glucose mmol/l

● Be aware of increased risk of venous thromboembolism in children with DKA, especially those with central venous catheters.

CEREBRAL OEDEMA

● In children with DKA susspect cerebral oedema if they have any of these early manifestation:-headache-agitation or irritability-unexpected fall in heart rate-increase blood pressure-deterioration in level of consciousness-abnormality of breathing pattern, e.g. respiratory pauses-oculomotor palsies-pupillary inequality or dilatation

● Cerebral oedema should be treated immediately :- MANNITOL 20% 0,5-1 g/kg over 10-15 minutes- HIPERTONIC SODIUM CHLORIDE 2,7% or 3% 2,5-5 ml/kg over 10-15 minutes

HONEYMOON PERIOD

● In patient with new onset DM1 who do not have DKA, the beta cell mass has not be completely destroyed. The remaining funcional beta cells seem to recover with insulin treatment, and they are again able to produce insulin.

● When this occure, insulin replacements decrease.

● This phase of disease is know as the honeymoon period. It starts in the first weeks of therapy and usually continues for a few months.

MANAGEMENT

● For the patient with new onset DM1, typical starting dosage are approximately 0,7 U/kg/ 24 hours.

● Patient in the honeymoon period may require 0,4-0,6 u/kg/24 hours.

● Prepubartal patient with a duration of DM longer than 1 to 2 years typically require 0,5-1,0 U/ kg/24 hours. During middle adolescens, when elevated GH concentrations produce relative insulin resistance, insulin requirements increase by 40% to 50%.

INSULIN● Human insulin analogues● Rapid-acting insulin analogues – Humalog, NovoRapid● Very long-acting insulin analogues – Lantus● Short-acting – Actrapid, Humulin S

INJECTION SITES

● Dawn phenomenonIt is normal rise in blood sugar as a person's body prepares to wake up. In the early morning hours, hormones (GH, cortisol, catecholamines) cause the liver to release large amounts of sugar into the bloodstream, Insulin control the rise ine the blood sugar.

● Somogyi effectIf the blood sugar level drops too low in the early morning hours ( 2-3 a.m.), hormones ( such as GH, cortisol, catecholamines) are released. This help reverse the low blood sugar level but may cause that the level is higher than normal in the morning.

● Many types of insulin differ in duration of action and time to peak effect.

● They can be use in various combination, depands of the needs and goals of the individual patient.

● Serum glucose concentration should be assessed before each meal, at bedtime, and at 2 to 3 am to provide information for adjustment of the regimen.

● Meal planning is crucial to control of glucose in DM1.

● Two s.c. Injecton per day of intermediate- acting insulin (NPH) and short acting insulin (regular, lispro, asprat insulin)- seldom used, needs a meal schedule and can be difficult coordination.

● Multiple injections of short-acting insuline given before meals in combination with a long-acting basal insulin (glargine) or with intermediate acting insulin (NPH) given at bedtime.

● Pumps provide a continuous s.c. infusion of short acting insuline- given by highly motivated to achieve tight control.

● Despite advance in technology, the management of diabetes is still cumbersome and insulin replacement not physiological.

● Insulin responses to changes in blood glucose are based upon intermittent blood glucose testing and corrections.

● Insulin is given into the system circulation whereas endogenous insulin is secretated into the portal vein.

● However, it is a crusial to normalize glucose levels in order to prevent long-term consequences of diabetes especially from micro-vasculopathies, leading to neuropathy, renal failure and blindness

The aims of long- term management are:

● Normal growth development● Maintaining as normal a home and school life as possible● Good diabetic control through knowladge and good

technique● Encouraging children to become self-reliant, but with adult

supervision until they are able to take responsibility● Avoidace of hypoglycaemia● To prevation of long- term

complications

Prevention of long-term complications

● Measurements of glycosylated hemoglobin reflect the average blood glucose concentration over the preceding 3 months. It should be mesured four times a year.

● Blood pressure- must be checked for evidence of hypertension.

● Renal disease- the detection of microalbuminuria is an early sign of nephropathy.

● Eyes- retinopathy or cataracts requiring treatment are rare in children but should be monitored annually after 5 years of dabetes from onset of pubarty.

● Feed- avoid tight shoes and traet any infections early

HYPEROSMOLAR HYPERGLYCEMIC STATE

● HHS is one of two serious metabolic derangements that occures in patient with DM1. It is most commonly seen in patient with DM2 who have some concomitant illness that leads to reduced fluid intake. Infections, stroke, myocardial infarction can cause this state.

● The basic mechanism is a relative reduction in effective circulating insulin with a concomitant rise in counterregulatory hormones. Most patient do not develop significant ketoacidosis. Insulin remains available in amounts sufficient to inhibit lipolysis and ketogenesis but not to prevent hyperglycemia. Osmotic diuresis causing a decrease in total body water.Hyperosmolarity itself may also decrease lipolysis (less free fatty acids),

● Diagnostic features of HHS may include the following:- plasma glucose level of 600 mg/dl or greater-effective serum osmolality of 320mOsm/kg or greater-profound dehydratation, up to an average of 9 L.-serum pH greater than 7,3-bicarbonate concentration greater than 15 mEq/L-small ketonuria and low absent ketonemia-some alteration in consciousness

● Treatment:- Fluid resuscitation with 0,9%saline at the rate of 15-20 ml/kg/h in first hour- The i.v. fluid should also include 20-40mEq/L of potassium chloride to treat hypokalemia, which is seen in patient with HHS.- Begin a continuous insulin infusion of 0,1 U/kg/h. If blood glucose concentration reaches 300mg/dl- decrease insulin infusion rate by 0,5-1U/H.

LACTIC ACIDOSIS

● It is a medical condition characterized by the buildup of lactate in the body, which results in an excessively low pH.

● Symptoms: nausea, vomiting, generalized muscle weakness and rapid breathing.

● Pathophysiology-Glucose is broken down to puryvate through glycolysis. Mitochondria can oxidaze the puryvate into water and carbon dioxide, which requires oxygen (the net result is ATP- energy carrier for cells, hydrogen cations are produced from ATP hydrolysis). If it is hypoxia, the mitochondria are unable to continue ATP synthesis. In this situation, glycolysis is increased to provide additional ATP. The excess purivate production is converted into lactate (anionic form of lactic acid) and release into the bloodstream and also hydrogen cations rises and causes acidosis.

● During exercise and some illness, lactate production is by the catecholamine- driven glycolysis that cells use when they cannot get enough energy from oxygen reactions.

● Sometimes lactatic acidosis occurs without hypoxia- e.g. in rare inborn errors of metabolism, when the mitochondria do not function at full capacity.

● Lactate is metabolized in liver (60%) and kidney (30%) to glucose

● Some lactate is metalized to CO2 and water ( Krebs cycle).

● Type A- decrease perfussion or oxygenetion-sepsis, SIRS, lung diseases,

● Type B1- underlying disease- liver failureType B2- medication (metformin), intoxication (cyanide)Type B3- inborn error of metabolism (glucose6phosphatase deficincy)

● Diagnosis:- serum lactate levels: 4-5 mEq/L (> 5 mmol/l)- pH< 7,35- bicarbonate less than 10 mmol/l- anion gap > 10 mmol/l- glucose blood concentration can be correct.

● Treatment:- oxygen- direct removal of lactate from the body- hemofiltration- effective management of the underlyin causes – eg sepsis- avoiding sodium bicarbonate ( unless it is pH< 7,0)

HYPOGLYCEMIA● Low blood sugar● Clinical features include – clumsinsess, trouble walking,

confusion, sweating, pallor, headache, seizures, coma● The most common cause is medication used to treat DM

such as insulin and sulfonylureas.● Definition:

- in people with diabetes- below 3,9 mmol/L (70 mg/dl)- in newborns- below 2,2 mmol/L (40 mg/dl) below 3,3 mmol/L (60 mg/dl) with symptoms- serum level below 2,8 mmol/L (50 mg/dl) after not eating and following exercise may be used.

● First eat or drink 15 grams of fast acting carbohydrate, wait 15 minutes, take another one if the blood sugar is below 70mg/dl

● Glucagon- subcutaneous, i.m, i.v. less than 20 kg- give 0,5mg; > 20kg- dose is 1mg.

● Short- term treatment consist of i.v. bolus od dextrose 10% 2,5 ml/kg → 1 ml/kg during 3 min, after that 0,2 mg/kg/min

Thank you :)

diabetes mellitus agnieszka krosnowska - … · diabetes mellitus it is a group of metabolic...

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