Type I and II Diabetes Mellitus

Type I Diabetes Mellitus

• This conditionresults from an absolute lack of insulin secretion.
• Autoimmune destruction of pancreatic islet cells (islets of Langerhans) contributes to the lack of insulin secretion.
• Ketoacidosis, marked by increased levels of circulating fatty acids, can lead to renal failure and circulatory collapse.
• Untreated Type I Diabetes can result in serious, chronic conditions like cardiovascular and nervous system damage.

Type II Diabetes Mellitus

• Insulin resistance is a key feature, where target cells become unresponsive to insulin, causing blood glucose levels to rise.
• The pancreas initially secretes more insulin, but hypersecretion leads to beta cell exhaustion and death.
• Eventually, there's a deficiency in insulin secretion combined with insulin resistance.
• It is possible to reverse insulin resistance through a healthy diet and exercise.
• Untreated, type 2 DM can result in the same chronic conditions as type 1 DM.

Signs and Symptoms of DM

• Fasting blood glucose levels greater than 126 mg/dL (x2)
• Polyuria
• Polyphagia
• Polydipsia
• Glucosuria
• Fatigue
• Weight loss (primarily in type 1 diabetes).

Complications of Diabetes

• Nephropathy
• Neuropathy
• Retinopathy (potentially leading to blindness)
• Atherosclerosis

Insulin Preparations

• Considerations include onset of action, time to peak effect, duration, and source.

Insulin

• Most insulin used today is human insulin.
• Insulin analogs are made by recombinant DNA technology.
• Insulin analogs are more effective, cause fewer allergies, and less resistance.
• Insulin analogs can be modified for rapid action (Humalog) or prolonged action (Lantus).

Insulins

• Rapid-acting insulins include lispro, aspart, and glulisine.
• Short-acting insulins are considered "regular" insulin.
• Medium- or intermediate-acting insulins include isophane, detemir and lente.
• Long-acting insulins include glargine and ultralente, and insulin detemir.
• Regular insulin can be bound to protamine (e.g., isophane) or zinc (e.g., lente, ultralente) to prolong its duration of action.
• Glargine insulin, despite being long-acting, appears as a clear solution.

Routes of Insulin Administration

• Insulin can be administered subcutaneously or intravenously.
• Only regular insulin can be given intravenously.

Insulin Side Effects

• Hypoglycemia can manifest as sweating, tachycardia, confusion, drowsiness, and convulsions.
• Lipodystrophy, the destruction of lipids over time can occur.
• Insulin allergy, like animal insulin or other ingredients can cause a reaction.
• Insulin resistance can develop.

Human Regular Insulin (Humulin R, Novolin R)

• Falls under Therapeutic Class of parenteral drug for diabetes and Pharmacologic Class of short-acting hypoglycemic drug.
• It helps maintain blood glucose levels within normal limits by promoting cellular uptake of glucose, amino acids, and potassium.
• This promotes protein synthesis, glycogen and fatty acid storage, and conserves energy by utilizing glucose and inhibiting gluconeogenesis.
• The drug is short acting and commonly used with intermediate or long-acting insulin for 24-hour glucose control.
• Used as monotherapy for lowering blood glucose in type 1 diabetes.
• Used in combination with oral antidiabetic drugs for type 2 diabetes.
• Human Regular Insulin can be used for the emergency treatment of DKA (diabetic ketoacidosis).
• It can be used for gestational diabetes.
• Ensure the patient has sufficient food and is not hypoglycemic prior to administration.
• Regular insulin is the only type of insulin allowed for IV injection.
• Rotate injection sites, using sites not normally used at home when hospitalized.
• Administer approximately 30 minutes before meals for optimal absorption.
• Pregnancy category B.
• Onset is 30-60 min subcutaneous or 15 min IV.
• Peak is 4-12 h subcutaneous or 30–60 min IV.
• Duration is 5-7 h subcutaneous or 30–60 min IV.
• Hypoglycemia is the most common adverse effect.
• Hypoglycemia may result from excess insulin, improper timing with food, or skipping meals and it includes tachycardia, confusion, sweating, & drowsiness.
• Lipohypertrophy can occur at injection sites; rotating sites can lessen this.
• Weight gain is a possible side effect.
• Exercise caution with insulin in pregnancy, chronic kidney disease (CKD), fever, and thyroid disease among older adults, children, or infants.
• It should not be administered to patients with hypoglycemia, and those with hypokalemia require careful monitoring.
• Alcohol, salicylates, monoamine oxidase inhibitors (MAOIs), anabolic steroids, and ACE inhibitors potentiate hypoglycemic effects.
• Corticosteroids, thyroid hormone, and epinephrine antagonize hypoglycemic effects.
• Furosemide or thiazide diuretics can increase serum glucose levels.
• Beta-adrenergic blockers may mask hypoglycemic reaction symptoms.
• May increase urinary vanillylmandelic acid (VMA) and interfere with liver tests and thyroid function tests.
• Can decrease levels of serum potassium, calcium, and magnesium.
• Garlic, bilberry, and ginseng may potentiate hypoglycemic effects of insulin.
• Overdose causes hypoglycemia, which is treated with oral glucose for mild cases and parenteral glucagon or IV glucose for severe episodes.

Drugs for Type 2 Diabetes

• Sulfonylureas: glyburide (Micronase) and glypizide
• Meglitinide: repaglinide
• Biguanides: metformin (Glucophage)
• Alpha glucosidase inhibitors: acarbose and miglitol
• Thiazolidenediones: rosiglitazone
• Sodium glucose cotransport inhibitors: canagliflozin (Invokana), dapagliflozin (Forxiga), and empagliflozin (Jardiance)
• Incretin enhancers
  • DPP4-inhibitors: saxagleptin (Onglyza)
  • GLP-1 agonists: semaglutide (Ozempic)

Biguanides

• Metformin (Glucophage) can be used in pediatric patients, using adult doses as reasonable.
• It inhibits hepatic glucose output and reduces peripheral insulin resistance in muscle.
• There is less risk of hypoglycemia with this drug.
• Weight tends to decrease or remain stable, and cholesterol and triglyceride levels decrease.
• May normalize ovulatory function in girls with PCOS.
• Risk of lactic acidosis, abdominal discomfort, nausea/vomiting, and decreased absorption of Vitamin B12/folic acid are all adverse effects.

Metformin (Fortamet, Glucophage, Glumetza, Others)

• Falls under Therapeutic Class of antidiabetic drug and Pharmacologic Class of Biguanide.
• It is a preferred oral antidiabetic drug for managing type 2 diabetes due to its effectiveness and safety.
• It is used alone or with other antidiabetic medications or insulin & approved for use in children age 10 years or older.
• regular-release tablets, solution (Riomet), and sustained-release forms (Fortamet, Glucophage XR, Glumetza) are all forms of this drug.
• It reduces fasting and postprandial glucose levels by decreasing hepatic glucose production and reducing insulin resistance, but does not promote insulin release from the pancreas.
• It does not cause hypoglycemia.
• It lowers triglyceride, total and LDL cholesterol, and promotes weight loss.
• It is used off-label to treat women with polycystic ovary syndrome by reducing insulin resistance.
• Make sure sustained-release tablets are swallowed whole and not crushed or chewed.
• Monitor fasting blood glucose levels every 3 months and adjust the dose accordingly.
• Discontinue if signs of acidosis are present.
• Pregnancy category B.
• Onset is less than 1h.
• Peak is 1-3 h (regular release); 4–8 h (extended release).
• Duration is 12 h (regular release); 24 h (extended release).
• Common adverse effects are GI related and include nausea, vomiting, abdominal discomfort, metallic taste, diarrhea, and anorexia.
• Headache, dizziness, agitation, and fatigue can occur.
• Unlike sulfonylureas, metformin rarely causes hypoglycemia or weight gain.
• Lactic acidosis is a rare, but potentially fatal, adverse effect.
• Patients with CKD or conditions at risk for increased lactic acid production are more at risk for this.
• Contraindicated in patients with advanced CKD due to potential toxicity.
• Contraindicated in patients with heart failure, liver failure, history of lactic acidosis, or concurrent serious infection.
• Hold 2 days prior to and 2 days after receiving IV radiographic contrast.
• Use caution in patients with anemia, diarrhea, vomiting or dehydration, fever, gastroparesis, GI obstruction, hyperthyroidism, pituitary insufficiency, trauma, pregnancy and lactation, and in older adults.
• Alcohol increases the risk for lactic acidosis.
• Captopril, furosemide, and nifedipine may increase the risk for hypoglycemia.
• IV radiographic contrast may cause lactic acidosis and acute renal failure.
• The following drugs may decrease renal excretion of metformin: amiloride, cimetidine, digoxin, dofetilide, midodrine, morphine, procainamide, quinidine, ranitidine, triamterene, trimethoprim, and vancomycin.
• Acarbose may decrease blood levels of metformin.
• Use with other antidiabetic drugs potentiates hypoglycemic effects.
• May cause false-positive results for urinary ketones.
• Decreases the absorption of vitamin B12 and folic acid, while garlic and ginseng may increase hypoglycemic effects.
• For overdose or development of lactic acidosis, hemodialysis can correct the acidosis and remove excess metformin.

Sulfonylureas

• 1st generation: chlorpropamide (Diabinese)
• 2nd generation: glyburide (Micronase) & glypizide (Glucotrol), glimepiride (Amaryl)
• 2nd generation are more potent, have fewer side effects, longer duration of action, and do not interact with protein-bound drugs.
• Promote insulin secretion by stimulating pancreatic beta cells.
• Block ATP-sensitive K+ channels to stimulate insulin release.
• Adverse effects: Hypoglycemia, GI distress, weight gain, aplastic anemia, leukopenia, thrombocytopenia.

Sodium/Glucose cotransporter 2 Inhibitors

• Empagloflozin (Jardiance) inhibits sodium/glucose cotransporter 2 in the proximal tubule, decreasing glucose absorption.
• Promotes weight loss.
• Reduces risk of CV disease in patients with DM and atherosclerotic heart disease.
• Side effects : acute kidney injury and GU infection.
• Contraindicated with eGFR < 30 mL/min/1.73 m2.

Incretins

• Hormones released into the blood by the intestines in response to food.
• They signal insulin secretion and stop glucagon production.
• GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1).

Incretin Enhancers

• Drugs that mimic the effects of incretins.
• Reduce food intake by decreasing gastric emptying and increasing the sense of "fullness".
• May be used as an alternative if metformin or sulfonylurea monotherapy is ineffective, but they have a high incidence of nausea/vomiting and diarrhea.
• Oral dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists.

Saxagliptin (Onglyza)

• It is a Dipeptidyl peptidase-4 (DPP-4) inhibitor.
• It breaks down glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide to increase insulin release.
• It's typically dosed once daily.
• Common side effects include upper respiratory infections, UTI, headache, and hypersensitivity reactions.
• It can increase hypoglycemia when given in combination with sulfonylureas.

Semaglutide (Ozempic)

• GLP-1 receptor agonist.
• Used for the treatment or prevention of type 2 diabetes in people who are obese.
• It is injected once a week.
• Some use it for weight loss although it is not FDA approved for this.
• Common side effects include nausea, vomiting, and diarrhea.
• A more serious side effect is thyroid cancer, pancreatitis, gall bladder disease, and kidney failure.