Discovery Curriculum: M2 Pathophysiology Type 1 Diabetes in Pediatric Patients

Handout -Session 5c – February 3, 2014 Monday PM Hour 4: T1DM pediatric – Auble

Pathophysiology of T1DM in children Type 1 Diabetes is an autoimmune disease that comprises about half of the patients we see in Pediatric Endocrinology. I don’t pretend to be an immunologist, so I’ll explain this at the level that we need to understand now. After an environmental trigger, an insult to the pancreatic beta cells results in antigen release (specifically GAD65), which are taken up by antigen presenting cells and presented to CD4 cells. Autoreactive T cells (T helper 1 cells, TH1) recruit cytotoxic CD8 cells, which attack the pancreatic beta cells in the setting of cytokines and massive release of GAD65 occurs. This causes the gradual destruction of the beta cell, which produces insulin. When 80-90% of the beta cells are destroyed the symptoms of diabetes occurs. Symptoms of new-onset Type 1 Diabetes: increased thirst (polydipsia), increased urination (polyuria), bedwetting (enuresis), weight loss, increased hunger (polyphagia), and fatigue.

Natural history of type 1 diabetes A person has to have a genetic predisposition to develop T1DM, specifically certain HLA haplotypes (DR3/4). There is an environmental trigger (still debated), but commonly thought to be a viral illness or possibly gut flora changes or food introduction. The beta cell is destroyed in the fashion described in the previous slide, and “pre-diabetes” occurs. Pre-diabetes or glucose impairment: does not meet strict criteria for diabetes, but the beta cell is starting to fail. Patient may have fasting blood sugars above 100 but not as high as 126, post-prandial blood sugars are not as high as 200 mg/dL. Diabetes: fasting BG >126 x 2, >200 x1, and/or positive oral glucose tolerance test.

Epidemiology of T1DM From 2001 to 2009, the prevalence of diabetes increased significantly (although recent data may reveal a slow-down). As of 2009, the rate of males to females continued to be equal for rates of Type 1 Diabetes. The largest population affected is non-Hispanic white, followed by African Americans, Hispanics, Asian Pacific Islanders, and Native Americans. The peak age for diagnosis is between 15-19 years and 10-14 years.

Some common electrolyte changes in untreated T1DM: Hyponatremia – osmotic dilution of plasma Hypokalemia – not a consistent finding Low “carbon dioxide” (i.e. bicarbonate) – ketoacidosis Phosphate: decreased phosphate intake and phosphaturia Low Na: -Hyperglycemia will increase the plasma osmolality, resulting in osmotic water movement out of the cells which lowers the serum sodium by dilution. -artifact in testing with hyperglycemia (calculate for real sodium level) Hyperkalemia: -Total body potassium depleted with elevated serum potassium. The osmotic diuresis and increased ketoacid excretion promote urinary potassium loss, while vomiting and diarrhea, if present, increase gastrointestinal potassium losses. -Insulin deficiency impairs potassium entry into the cells, and hyperosmolality, which pulls water and potassium out of the cells, tends to raise the serum potassium concentration. Low bicarb: Lipolysis (releases fatty acids) and ketogenesis due to insulin deficiency collectively contributes to the development of low bicarb. Bicarb is used as a buffer for the acidosis at the level of the kidney and is used up. Phosphate: Negative phosphate balance because of decreased phosphate intake and phosphaturia caused by the glucosuria-induced osmotic diuresis. Metabolic acidosis cause a shift of phosphate out of the cells, so phos can look low, normal, or elevated.

A) When a person ingests a glucose load (75 g), plasma glucose, shown by the green curve, rises slowly, reflecting the intestinal uptake of the glucose. In response, the pancreatic β cells secrete insulin, and plasma insulin, shown by the solid red curve, rises sharply. In a patient with type 1 diabetes, the same glucose load as that in A causes glucose to rise to a higher level and to remain there longer. The reason is that insulin rises very little in response to the glucose challenge, and the cells are unable to transport the glucose. The diagnosis of diabetes is made if the plasma glucose is higher than 200 mg/dL at the second hour. If the glucose challenge is given intravenously, then the plasma glucose rises much more rapidly than it does with an oral glucose load. Following this acute phase, the cells secrete both presynthesized and newly manufactured insulin in the chronic phase, which lasts as long as the glucose challenge.

Biochemistry of Ketoacidosis Diabetic ketoacidosis occurs in the presence of absolute insulin deficiency. There is increased liver-production of glucose by gluconeogenesis and decreased uptake by cells. Blood sugar rises dramatically, which causes as glucose spilling in the urine (glycosuria) when BG is >180 mg/dL. This causes osmotic diuresis and dehydration and possibly shock. Lack of energy substrate in the cells causes lipolysis and ketone production. Ketoacidosis makes people nauseated, which causes vomiting and worsens dehydration. The compensatory hyperpnea (Kussmaul respiration) is the body’s attempt to compensate for the metabolic acidosis by “blowing off” more CO2.

There are various forms of insulin available that have variable time of onset and length of action. Each patient needs basal (long-acting or background) insulin and insulin with meals (shorter acting). Historically, NPH and Regular were used as twice daily to cover both meals (regular) and background insulin (NPH). People have to eat a certain amount at certain times or they are at risk for low blood sugar. Currently, the best practice of treating diabetes is multiple daily injections (MDI) which includes one daily basal injection (glargine, detemir) and covering carbohydrates with multiple short-acting injections (aspart, lispro). Because there is a lack of insulin, oral agents are not sufficient to treat type 1 diabetes. These medications tend to work by releasing more stored insulin or increasing peripheral sensitivity in patients with Type 2 diabetes, which is not a concern for T1DM. For continuous subcutaneous infusion by insulin pump, we use short-acting insulin, either aspart or lispro. It acts as both the basal insulin and boluses are given for meals to cover carbohydrates. This allows for titration and finer management of blood sugars.

Insulin overdose Insulin overdose causes hypoglycemia (blood sugar <70 mg/dL). This can cause mild symptoms of shakiness, headaches, dizziness, sweatiness, tachycardia, hunger, or fatigue. It is the response to increased sympathetic tone. It is treated with oral fast-acting carbohydrates (juice, candy) and rechecking blood sugar in 15 minutes until rising. If patient has moderate hypoglycemia, which causes neuroglycopenic symptoms, patients experience confusion, combativeness, poor coordination, slurred speech. Treatment usually includes fast-acting carbohydrates, such as frosting or sugar-gel, given orally or in the buccal mucosa. For severe hypoglycemia, which results in stupor, seizure, and coma, patients should receive emergency care with glucagon injections (after EMS is called). Mild hypoglycemia is counteracted by increased sympathetic tone (adrenergic response), which results in shakiness, hunger, dizziness, heart racing. It is treated with oral fast acting carbohydrates. Moderate hypoglycemia is characterized by neuroglycopenic symptoms: confusion, combativeness, slurred speech. Treatment is given by oral fast acting carbohydrates, often given in the buccal mucosa by a caregiver. Severe hypoglycemia can results in seizure, coma, and is treated with intramuscular glucagon and calling 911.

Session 5c – Bethany Auble, MD Auble/5c/T1D peds

Case You are seeing Bobby, a 7-year-old boy, in your outpatient clinic for concerns of fatigue and increased thirst. Mother reports he has had less energy than usual, and unable to keep up with his peers. His appetite has been good. He has had a recent growth spurt but his weight has remained the same. You probe further and find he has had 2 episodes of bedwetting over the last 2 weeks. He has been potty trained since 4 years of age and has not had any accidents since then. Mom believes his clothes have become loose in the past several weeks.

Case – Question 1 You suspect Type 1 diabetes mellitus. Understanding the pathophysiology of the disease, which would be most consistent with this diagnosis? Pancreatic alpha cells are systematically destroyed Bobby ate too many Christmas cookies **TH1 and CD8-mediated destruction of beta cells. Insulin resistance led to inability to respond to carbohydrates. His bedwetting is due to vasopressin deficiency.

Case - continued You obtain the following fasting laboratory tests: Glucose 534 mg/dL (60-100) Chloride 112 mEq/L (98-108) Sodium 131 mEq/L (135-145) Creatinine 0.9 mg/dL (0.5-1.06) Potassium 5.5 mEq/L (3.5-5) Hemoglobin 13.5 g/dL (10.5-14) Carbon dioxide 19 mEq/L (20-28) Urine specific gravity 1.015 (1.001-1.035)

Case – Question 2 What is the best course of treatment for Bobby? **Glargine and lispro insulin Metformin therapy Diet and exercise Glipizide Glitazone

Case – Question 3 Which of the following would be a better choice for a bedtime snack for 30g? 2 pieces of white toast 8 oz. orange juice **10 Triscuit crackers with cheese slices 30 Skittles Diet caffeine-free coke

Pearls for T1DM (Pediatrics) Type 1 Diabetes is an autoimmune diseases caused by T Helper (TH1) cell-recruitment of cytotoxic CD8 cells and destruction of beta-cells with cytokines. Symptoms of T1DM include increased thirst, urination, hunger, weight loss and fatigue. Diagnosis is made by a random blood glucose >200 mg/dL, two fasting blood glucose values of >126 mg/dL, or a positive oral glucose tolerance test Diabetes ketoacidosis (DKA) is characterized by severe hyperglycemia, ketoacidemia, and dehydration leading to hypovolemic shock. The most common regimen of insulin is multiple daily injections (MDI): long-acting insulin, such as glargine or detemir, and short-acting insulin with meals, such as lispro or aspart.