Diabetes Mellitus: Metabolic Consequences and Management

• Glucagon regulates the amount of glucose in the bloodstream.

Glycogen

• Glycogen is involved in glucose regulation during prolonged fasting or starvation.
• Insufficient glucose intake can lead to glycogen activation.
• Hypoglycemia can develop in the bloodstream due to a lack of glucose.
• When cells sense starvation, the liver breaks down its glycogen storage.

Incretins (GIP and GLP-1)

• Glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin release at normal glucose levels.
• Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release when glucose levels are >90 mg/dL.

Amylin

• Amylin slows gastric emptying, which promotes a feeling of fullness.

Glycogenolysis vs. Gluconeogenesis

• Glycogenolysis occurs in the liver, breaking down stored glycogen and releasing glucose into the bloodstream.
• Gluconeogenesis, also in the liver, converts fats/proteins into endogenous glucose.

Ketones

• The presence of ketones in urine or blood indicates an increase in free fatty acids, which are then converted to ketones due to lipid breakdown.

Type 1 vs. Type 2 Diabetes Mellitus (DM)

• Type I DM involves the loss of pancreatic beta cells secretion of insulin (autoimmune), and treatment requires mandatory insulin replacement with strict dietary control.
• Type II DM involves insulin resistance, loss of incretin effect, and beta cell dysfunction (genetics, lifestyle); treatment includes oral anti-diabetic medications, non-insulin injectables, or insulin combined with a reduced calorie diet and exercise.

Manifestations of DM

• T1DM onset is more abrupt and may present with diabetic ketoacidosis (DKA).
• T2DM has a gradual onset.
• Hallmark symptoms of DM: polyuria, polydipsia, and polyphagia.
• Other symptoms include fatigue, vision changes, non-healing sores, frequent infections (genital, vaginal, skin, and gums), numbness, and tingling in legs and feet (peripheral neuropathy).

Gestational Diabetes

• Infants of mothers with gestational diabetes may experience metabolic abnormalities, stillbirth, macrosomia, and neonatal hypoglycemia.
• Mothers with gestational diabetes can later develop T2DM or insulin resistance.
• Management includes dietary counseling, exercise, blood glucose/ketone monitoring, and possibly insulin.

Markers for Diagnosing DM

• Hemoglobin A1c >6.5% reflects blood glucose control over the lifespan of red blood cells (90-120 days) and is not affected by short-term variations in blood glucose.
• Fasting plasma glucose (FPG) >126 mg/dL, with no caloric intake for >8 hours.
• Two-hour plasma glucose >200 mg/dL during an oral glucose tolerance test (OGTT) using 75g glucose in water.
• Random plasma glucose >200 mg/dL with classic symptoms of hyperglycemia.

Goals for Patients with DM

Glycemic

• HbA1c should be <7% (or <8% if elderly or have a history of severe hypoglycemia).
• Fasting plasma glucose for outpatient: 80-130 mg/dL.
• Fasting plasma glucose for inpatient: 140-180 mg/dL.
• Post-prandial glucose (1-2 hours after a meal): <180 mg/dL.

Blood Pressure/Lipids

• Blood pressure goal: <130/80 mmHg or <140/90 mmHg.
• Total cholesterol: <200 mg/dL.
• LDL: <100 mg/dL.
• HDL: >60 mg/dL.
• Triglycerides: <150 mg/dL.

Renal Function

• Kidneys with damage leak small amounts of albumin into urine.
• Albumin/creatinine ratio should be <30 mcg/mg (random collection).
• The multiple goals for patients with DM are to prevent complications.

DM Complications

• Microvascular complications occur due to the thickening of the basement membrane of capillaries which reduces blood flow in narrow vessels, leading to kidney damage (nephropathy), blindness (retinopathy), and neuropathies.
• Macrovascular complications result from sustained hyperglycemia and altered lipid metabolism, leading to atherosclerosis.

Oral Hypoglycemic Agents

Biguanide: Metformin

• Metformin enhances glucose uptake by tissues (insulin sensitivity), decreases gluconeogenesis, and decreases the amount of glucose absorbed from the intestines.
• Adverse effects include gastrointestinal issues such as nausea, vomiting, and diarrhea, which can lead to weight loss; vitamin B12 and folic acid deficiency; lactic acidosis (BBW).
• Monitor and provide supplementation if needed for vitamin B12 and folic acid deficiency.
• Administer with food to reduce gastrointestinal issues.

Sulfonylureas: Glipizide

• Glipizide stimulates insulin secretion from the pancreas by binding to pancreatic beta receptors.
• The most significant risk with sulfonylureas is hypoglycemia.
• Clinical considerations: Take 30 minutes before breakfast; hold the dose if the patient is not eating.
• Drug interactions: Alcohol- disulfiram like reaction (intense nausea and vomiting, flushing, palpitations).

Thiazolidinedione (TZDs): Pioglitazone

• Pioglitazone activates the PPAR-gamma gene, increasing insulin sensitivity and glucose uptake by 30-50%, and decreases liver gluconeogenesis.
• Adverse effects include fluid retention, heart failure (BBW), increased LDL levels, hepatotoxicity, risk of bone fractures, and bladder cancer.
• May cause ovulation in some females.

SGLT-2 Inhibitors: Canagliflozin

• Canagliflozin inhibits the sodium-glucose co-transporter in the proximal renal tubule, reducing the reabsorption of filtered glucose, which results in glucose excretion in the urine.
• Adverse effects: infections, cystitis, candidiasis, Fournier gangrene, polyuria, dizziness, risk of hypotension, and hypovolemia.

Non-Insulin Injectable: Incretin Mimetic Exenatide

• Exenatide is a GLP-1 receptor agonist that increases glucose-dependent insulin secretion and has the same amylin-like effects.
• BBW: certain types of thyroid cancer
• Adverse effects: nausea, vomiting, diarrhea, pancreatitis.
• Should not be used in patients with a history of pancreatitis, renal impairment, or GI issues.
• Immediate release is administered 60 minutes prior to morning and evening meals, with oral medications given one hour before or two hours after exenatide IR.
• Extended release is given once a week regardless of meals or time of day and should be kept in the refrigerator.

Ways to Improve Glucose Use by Organ

• Pancreas: Increases insulin secretion through Glipizide, and increases amylin secretion through Pramlintide.
• Intestines: Slows glucose absorption through Acarbose, and increases incretin effect through Sitagliptin and Exenatide.
• Liver: Inhibits gluconeogenesis through Metformin and Pioglitazone.
• Kidneys: Increases glucose excretion through urine through Canagliflozin.
• Skeletal and Adipose Tissues: Enhances insulin sensitivity through Metformin and Pioglitazone.

Insulin Overview

• Four types of insulin: rapid-acting, short-acting, intermediate-acting, long-acting.
• Characterized by bolus and basal.
• Insulin can be considered for T2DM patients.
• The largest adverse effect of insulin use is hypoglycemia.
• Drug interactions: Sulfonylureas, pramlintide, and alcohol have additive hypoglycemic effects with concurrent use, requires monitoring of serum glucose levels and adjusting insulin or oral hypoglycemic medication doses.
• Thiazide diuretics and glucocorticoids can raise blood glucose levels and counteract the effects of insulin, which requires higher insulin doses.
• Insulin can be administered subcutaneously.
• Regular insulin can be given IV push or IV infusion when needed (1 unit/ml in 0.9% NS).
• Lipohypertrophy is scar tissue that builds up over time by not rotating injection sites.
• Rotate injections, leaving 1 inch between administrations, and use the same general area for consistent absorption.
• Mixed insulin has a larger number that is intermediate-acting insulin, and a smaller number that is rapid or regular insulin.
• Must give right before meals twice daily.
• Advantage of a basal/bolus regimen: more flexible for patient mealtimes, and mimics normal pancreas secretions.
• Disadvantage of a basal/bolus regimen: multiple injections and cannot mix insulins.

Insulin Storage

• Opened vials should be stored in the refrigerator until the expiration date, and should not be frozen
• Used insulins can be stored at room temperature (between 59-86 degrees); discard after 30 days.

Hypoglycemia

• Level <70 mg/dL
• Caused by overdose of insulin, too little foot, V/D, alcohol intake, strenuous exercise and childbirth
• General signs and symptoms include shaking/trembling, faster HR, extreme hunger, sweating, confusion/difficulty concentrating and dizziness
• Treat by providing a patient-centered plan

DKA

• DKA is a severe manifestation of insulin deficiency.
• Manifestations include polyuria, polydipsia, abdominal pain, Kussmaul respirations, nausea, vomiting, tachycardia, dehydration, altered mental status, and fruity (acetone) breath.
• Management options include fluid and electrolyte replacement and IV regular insulin therapy to slowly stabilize blood glucose.
• Checking potassium levels, and correcting acidosis are pertinent

HHS

• Management options include controlled rehydration and monitoring serum osmolality.

Explore the metabolic consequences of uncontrolled diabetes, the mechanisms of action for medications like metformin and glucagon, and the roles of incretins and amylin in glycemic control. Learn about metabolic processes during starvation and the significance of ketone presence in urine.