Diabetes mellitus (DM) & DKa

Stephen Satyanand RamJuly 22nd 2016Dr. C Bowman

Diabetes mellitus (DM)• commonly referred to as diabetes(sugar)• is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period• is due to either the pancreas not producing enough insulin (insulin deficiency) •  or the cells of the body not responding properly to the insulin produced. (insulin resistance)

Epidemiology

• As of 2013, 382 million people have diabetes world wide.Type 2 makes up about 90% of the cases. This is equal to 8.3% of the adult population with equal rates in both women and men.• Diabetes mellitus occurs throughout the world but is more common (especially type 2) in more developed countries. The greatest increase in rates was expected to occur in Asia and Africa, where most people with diabetes will probably live in 2030.The increase in rates in developing countries follows the trend of urbanization and lifestyle changes, including a "Western-style" diet. 

Rates of Diabetes worldwide

Main Types of DM• Type 1 DM : results from the pancreas's failure to produce enough insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes".• Type 2 DM: begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop. The primary cause is excessive body weight and due to sedentary life style.• Gestational diabetes: is the third main form and occurs when pregnant women without a previous history of diabetes develop high blood-sugar levels.

Type 1• Type 1 diabetes mellitus is characterized by loss of the insulin-

producing beta cells of the islets of Langerhans in the pancreas, leading to insulin deficiency.• This type can be further classified as immune-mediated or

idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which a T-cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin.• It causes approximately 10% of diabetes mellitus cases in North

America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages

• "Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe the dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used. Still, type 1 diabetes can be accompanied by irregular and unpredictable high blood sugar levels, frequently with ketosis, and sometimes with serious low blood sugar levels. Other complications include an impaired counter regulatory response to low blood sugar, infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's disease). These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.

Type 2 DM is the most common type of diabetes mellitus.In the early stage of type 2, the predominant abnormality is reduced insulin sensitivity. At this stage, high blood sugar can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce the liver's glucose production.

Type 2 DM is due primarily to lifestyle factors and genetics] A number of lifestyle factors are known to be important to the development of type 2 DM, including obesity (defined by a bod mass index of greater than 30), lack of physical activity, poor diet, stress, and urbanization. Excess body fat is associated with 30% of cases in those of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific Islanders. Even those who are not obese often have a high waist–hip ratio.

Type 2

Comparison of type 1 and 2 DM

Gestational diabetes• Gestational diabetes mellitus (GDM) resembles type 2

DM in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness.

• It occurs in about 2–10% of all preganacies and may improve or disappear after delivery.

•  However, after pregnancy approximately 5–10% of women with gestational diabetes are found to have diabetes mellitus, most commonly type 2.

•  Gestational diabetes is fully treatable, but requires careful medical supervision throughout the pregnancy. Management may include dietary changes, blood glucose monitoring, and in some cases, insulin may be required.

Risk to the unborn fetus in GDM•  untreated gestational diabetes can damage the health of the

fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital heart and central nervous system abnormalities, and skeletal muscle malformations.

• Increased levels of insulin in a fetus's blood may inhibit fetal surfactant production and cause respiratory distress syndrome. A high blood bilirubin level may result from red blood cell destruction.

• In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function.

• A Caesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia

Sings and symptomsIndividuals can experience different signs and symptoms

of diabetes, and sometimes there may be no signs. Some of the signs commonly experienced include:

•Frequent urination (polyuria)•Excessive thirst (polydipsia) •Increased hunger (polyphagia)•Weight loss•Itchy skin (pruritus) •Fatigue •A tingling sensation or numbness in the hands or feet•Blurred vision•Frequent infections•Slow-healing wounds

• Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, muscle, and adipose tissue.

• Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.

• The body obtains glucose from three main places: the intestinal absorption of food, the breakdown of glycogen, the storage form of glucose found in the liver, and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body.

Pathophysiology

Diagnosischaracterized by recurrent or persistent high blood sugar, and is diagnosed by demonstrating any one of the following

• Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)

• Plasma glucose ≥ 11.1 mmol/l (200 mg/dl) two hours after a 75 g oral glucose load as in a glucose tolerance test

• Symptoms of high blood sugar and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)

• Glycated hemoglobin (HbA1C) ≥ 48 mmol/mol (≥ 6.5 DCCT %)

ManagementManagement concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications (insulin in the case of type 1 diabetes; oral medications, as well as possibly insulin, in type 2 diabetes).-Medications-Dietary and exercise modification-Regular complication monitoring-Self monitoring of blood glucose-Control of BP and lipid level

TreatmentPharmacological therapy

-Insulin (Type 1 and Type 2 DM)-Sulfonylurea (Type 2 DM)-Biguanides (Type 2 DM)-Meglitinides (Type 2 DM)-Thiazolidinediones Glitazones (Type 2 DM)-a-Glucosidase inhibitors (Type 2 DM)

Insulin

Strength -The number of units/mle.g. U-100 , U-20, U-10

Source -Pork: -Human (recombinant DNA technology)

Onset and duration of effect

Changing the properties of insulin preparation can alter the onset and duration of action

-Lispro: (Monomeric) absorbed to the circulation very rapidly

-Aspart:(Mono- and dimeric) absorbed to the circulation very rapidly

-Regular: (Hexameric) absorbed rapidly but slower than lispro and aspart

Rapid-acting insuline.g. Insulin lispro and insulin aspart

Short-acting insuline.g. Regular insulin

Intermediate-acting insuline.g. NPH and Lente insulin

Long-acting insuline.g. Insulin Glargine

How much insulin ?-A good starting dose is 0.6 U/kg/day-The total dose should be divided to:- 45% for basal insulin- 55% for prandial insulin

The prandial dose is divided to-25% pre-breakfast- 15% pre-lunch- 15% pre-supper

Example: For a 50 kg patient

-The total dose = 0.6X50 = 30 U/day- 13.5 U for basal insulin (45% of dose)

- Administered in one or two doses

- 16.5 U for prandial insulin (55% of dose)The 16.5 U are divided to:

-7.5 U pre-breakfast (25%)- 4.5 U pre-lunch (15%)- 4.5 U pre-supper (15%)

SulfonylureasStimulate the pancreatic secretion of insulinClassification:First generation

•e.g. tolbutamide, chlorpropamide, and acetohexamide•Lower potency, more potential for drug interactions and side effects

Second generation•e.g. glimepiride, glipizide, and glyburide•higher potency, less potential for drug interactions and side effects

All sulfonylurea drugs are equally effective in reducing the blood glucose when given in equipotent doses

Biguanides Metformin (Glucophage)

Pharmacological effect–Reduces hepatic glucose production–Increases peripheral glucose utilization

Adverse effects–Nausea, vomiting, diarrhea, and anorexia

–As a precaution metformin should not be used in patients with renal insufficiency, CHF, conditions that lead to hypoxia

pancreas transplant is occasionally considered for people with type 1 diabetes who have severe complications of their disease, including end stage kidney disease requiring kidney transplantation.

Weight loss surgery in those with obesity and type two diabetes is often an effective measure. Many are able to maintain normal blood sugar levels with little or no medications following surgery and long-term mortality is decreased. There however is some short-term mortality risk of less than 1% from the surgery. The body mass index cutoffs for when surgery is appropriate are not yet clear. It is recommended that this option be considered in those who are unable to get both their weight and blood sugar under control.

Surgery

Complications• The major long-term complications relate to damage to blood vessels.

Diabetes doubles the risk of cardiovascular disease and about 75% of deaths in diabetics are due to coronary artery disease. 

• Other "macrovascular" diseases are stroke, and peripheral vascular disease.

• The primary complications of diabetes due to damage in small blood vessels include damage to the eyes, kidneys, and nerves.

• Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and blindness. 

• Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplant.

• Damage to the nerves of the body, known as diabetic neuropathy,

DKA (Ketoacidosis) & KetonesDKA (Ketoacidosis) & Ketones

Diabetic ketoacidosis (DKA) is a serious condition that can lead to diabetic coma (passing out for a long time) or even death. Is a complex metabolic state of hyperglycemia, ketosis, and acidosis. Diabetic ketoacidosis results from untreated absolute or relative deficiency of insulin in type 1 or type 2 diabetes mellitus, respectively.• When your cells don't get the glucose they need for energy, your body begins to burn fat for

energy, which produces ketones.• Ketones are chemicals that the body creates when it breaks down fat to use for energy. The

body does this when it doesn’t have enough insulin to use glucose, the body’s normal source of energy.

• When ketones build up in the blood, they make it more acidic. They are a warning sign that your diabetes is out of control or that you are getting sick.

What are the Warning Signs of DKA?

Early symptoms include the following:•Thirst or a very dry mouth•Frequent urination•High blood glucose (blood sugar) levels•High levels of ketones in the urine

Then, other symptoms appear:•Constantly feeling tired•Dry or flushed skin•Nausea, vomiting, or abdominal painDifficulty breathing•Fruity odor on breath•confusion 

Laboratory tests • Serum glucose level:Serum glucose (eg, Accu-Chek, Dextrostix) determination of hyperglycemia provides the opportunity for rapid diagnosis and treatment of diabetic ketoacidosis (DKA). However, a urine analysis (dip for sugar and ketones) is also acceptable.• Serum potassium level:This is the most important electrolyte disturbance in patients with severe diabetic ketoacidosis.• Glycosylated hemoglobin: In a patient with known diabetes, high percentages of glycosylated hemoglobin (Hgb A1C) indicate poor compliance with insulin therapy.

• CBC countNote that an increased WBC count may be a response to stress in diabetic ketoacidosis and not necessarily a sign of infection.• Other studies include the following:• Obtain serum sodium, chloride, bicarbonate, BUN, creatinine, magnesium,

calcium, and phosphate levels• Urine glucose, ketones, and osmolality• Serum osmolality• Blood, urine, and throat cultures

Pathophysiology• Hyperglycemia results from impaired glucose uptake because of insulin

deficiency and excess glucagon with resultant gluconeogenesis and glycogenolysis.

• Glucagon excess also increases lipolysis with the formation of ketoacids. Ketone bodies provide alternative usable energy sources in the absence of intracellular glucose.

• The ketoacids (acetoacetate, beta-hydroxybutyrate, acetone) are products of proteolysis and lipolysis.

• Hyperglycemia causes an osmotic diuresis that leads to excessive loss of free water and electrolytes. Resultant hypovolemia leads to tissue hypoperfusion and lactic acidosis.

• Ketosis and lactic acidosis produce a metabolic acidosis; however, supplemental bicarbonate is not recommended.

• Acidosis usually resolves with isotonic fluid volume replenishment and insulin therapy. A pediatric trial of bicarbonate in severe metabolic acidosis during DKA (pH < 7.15) showed no benefit when compared with placebo.

•  Indeed, multiple studies suggest that bicarbonate therapy may cause paradoxical intracellular acidosis, worsening tissue perfusion and hypokalemia, and cerebral edema.

Management With current medical therapy, diabetic ketoacidosis has a 2-5% mortality rate. Mortality results from the precipitating underlying cause, which is primarily cerebral edema. Cerebral edema occurs in 0.3-1% of all episodes of diabetic ketoacidosis.• Provide oxygen and advanced airway management in

patients with diabetic ketoacidosis (DKA), if needed.• Monitor the patient.• Provide isotonic intravenous fluids (eg, isotonic sodium

chloride solution or lactated Ringer solution).• Electrolyte replacement.

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population-based study on the risk of coma, ketoacidosis and hypoglycemia in patients with celiac disease and type 1 diabetes. Acta Diabetol. 2015 Sep 24. [Medline].

Hsia DS, Tarai SG, Alimi A, Coss-Bu JA, Haymond MW. Fluid management in pediatric patients with DKA and rates of suspected clinical cerebral edema. Pediatr Diabetes. 2015 Aug. 16 (5):338-44. [Medline].

Wolfsdorf J, Glaser N, Sperling MA; American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. 2006 May. 29(5):1150-9. [Medline].