Insulin Functions in the Liver

Insulin and Oral Hypoglycemic Agents

• Diabetes mellitus (DM) is a group of diseases characterized by high blood glucose levels, resulting from defects in insulin production, insulin action, or both.
• Symptoms of diabetes include frequent urination, excessive thirst, extreme fatigue, blurred vision, slow-healing cuts/bruises, weight loss despite increased food intake, and tingling/numbness in hands and feet.
• Etiology (causes) of DM include increased insulin resistance and/or decreased insulin production.
• Diagnosis involves measuring hyperglycemia (high blood sugar) through random, fasting, and post-glucose-load tests. HbA1c is also used as a long-term measure of average blood sugar levels.
• Drug interactions can affect glucose homeostasis. Some drugs may cause hypoglycemia (low blood sugar), while others can cause hyperglycemia (high blood sugar). Examples of drugs influencing glucose levels include beta-adrenergic antagonists, ethanol, salicylates, sulfonamides, lithium, epinephrine, glucocorticoids, oral contraceptives, clonidine, and calcium channel blockers.

Actions of Insulin

• On the liver: Insulin inhibits glycogenolysis, gluconeogenesis, and ketogenesis. It increases glucose uptake and glycogen synthesis, and triglyceride synthesis.
• On muscle: Insulin increases amino acid transport and protein synthesis, as well as glucose uptake and glycogen synthesis.
• On adipose tissue: Insulin inhibits the breakdown of intracellular triglycerides, promotes their storage, and stimulates glucose uptake.

Types of Diabetes

• Type 1 Diabetes Mellitus (IDDM): caused by autoimmune destruction of beta cells in the pancreas. Features extremely low or undetectable insulin levels and cannot be stimulated. Commonly diagnosed in children and requiring insulin for treatment. A characteristic feature is the potential for ketoacidosis (build-up of ketones in the blood). Accounts for approximately 10% of cases.
• Type 2 Diabetes Mellitus (NIDDM): caused by decreased responsiveness of peripheral tissues to insulin, subnormal insulin levels, and blunted insulin response upon stimulation. Typically diagnosed in adults and often linked to overweight or obesity. Insulin is not always needed, and the condition is frequently manageable through diet, exercise, or oral antidiabetic drugs. Accounts for roughly 90% of cases.

Therapeutic Overview

• Type 1 DM: Treatment focuses on insulin, consistent dietary composition and timing, and exercise.
• Type 2 DM: Treatment involves diet (weight reduction), exercise, oral anti-diabetic drugs, and/or insulin.

Treatment Objectives

• The goal of diabetes therapy is to normalize blood glucose levels before, during, and after meals.
• Blood glucose levels provide a useful indication of the varied metabolic abnormalities in diabetes.

Pharmacological Targets of Drugs Used in the Treatment of DM

• Insulin and analogues: target the insulin receptor.
• Sulfonylureas, meglitinides, and nateglinide: target sulfonylurea receptors associated with ATP-sensitive K+ channels in beta cells.
• Biguanides: act through multiple mechanisms of action that aren't fully understood.
• Thiazolidinediones: target PPARγ (peroxisome proliferator-activated receptor gamma).
• a-glucosidase inhibitors: target a-glucosidases.

Optimal Glycemic Control

• A normal 24-hour profile of insulin secretion shows fluctuations related to meals, with higher insulin concentrations post-prandial (and then decreasing) and lower levels at night.

Types of Insulin

• Intermediate or long-acting insulins are used to emulate basal (constant background) insulin secretion.
• Short or ultra-short-acting insulins are used to emulate meal-stimulated insulin secretion.
• Various types of insulin (e.g., lispro, aspart, regular, NPH, lente, ultralente, glargine) have different onset, peak, and duration of action.

Insulin Preparations (Properties)

• Insulin preparations differ in their onset, peak, and duration of action. This table summarizes some examples.

Insulin Regimens

• Intensive regimens involve basal plus bolus doses.
• Conventional regimens involve specific doses before meals.

A Typical "Intensive" Regimen (and Variations)

• Intensive regimens utilize intermediate-acting and short-acting insulin to mimic normal patterns of insulin secretion.

Advantages of Intensive Regimens

• Better glucose control translates to better outcomes (fewer complications).
• This approach is more flexible.
• It includes a greater risk of hypoglycemia.
• The approach is more demanding on the patient.

Intensive treatment for whom?

• Type 1 and some Type 2 patients demonstrate consistent motivation and ability to manage the regimen.
• Pregnant patients may initially require an intensive approach as hormonal changes can affect blood sugar control.

A Typical BD Regimen (Basal-Bolus)

• This regimen involves intermediate+short-acting insulin doses to mimic normal basal and prandial insulin secretion.

Some Examples of Insulin Therapy

• Various insulin administration methods and timings are used.

Other Insulin Uses

• Insulin infusions (IV) can be used to treat ketoacidosis, especially during surgery or childbirth.
• Continuous subcutaneous insulin infusions (with portable pumps) are used as an option in some cases.

Other Considerations

• Earlier insulin forms were sourced from pigs and cows.
• Now, human insulin is the standard, offering reduced allergic reactions to non-human sources.

Adverse Reactions to Insulin Therapy

• Hypoglycemia (low blood sugar) can occur when awake or sleeping; often caused by overdose or skipping meals.
• Insulin allergy and resistance can also be adverse reactions.

Insulin Dose Selection

• Appropriate doses are based on patient needs, including blood glucose levels and HbA1c (long-term glucose control).
• Initial doses are often conservative and adjusted as needed.

Glucagon Rescue

• Glucagon is an emergency injection used for severe diabetic hypoglycemia.
• Glucagon is used to increase blood glucose.

Oral Anti-Diabetic Drugs: Biguanides

• Metformin is a biguanide used for the treatment of type 2 diabetes.
• General properties include reducing hepatic gluconeogenesis, increasing glycolysis and glucose uptake in peripheral tissues, reducing glucose absorption, and reducing glucagon levels.
• Potential side effects include gastrointestinal issues, and lactic acidosis, particularly in patients with impaired liver or kidney function, so caution is warranted. Metformin should be used cautiously in such patients.

Oral Anti-Diabetic Drugs: Sulfonylureas

• Sulfonylureas stimulate insulin secretion.
• General properties include increasing insulin secretion by decreasing K+ efflux and increasing insulin receptors and responsiveness in peripheral tissues, reducing glucagon levels.

Secretagogues: Glinides

• Repaglinide stimulates a rapid but short-lived insulin release.
• Has a similar efficacy to sulfonylureas (in terms of A1C lowering).
• Side effects: hypoglycemia, caution with hepatic impairment
• Often used in combination with metformin.

5-Thiazolidinediones

• Pioglitazone and Rosiglitazone are agonists for PPARγ, increasing insulin sensitivity in target tissues.
• Side effects can include fluid retention (so may be contraindicated in heart failure), weight gain, and potential for liver toxicity.

α-Glucosidase Inhibitors

• Acarbose and Miglitol reduce intestinal carbohydrate absorption by inhibiting glucosidases.
• Side effects can include flatulence, diarrhea, and abdominal pain.
• Hepatic toxicity has been a concern in some cases.

Old Approach to Oral Agents (Treatment Sequencing)

• A phased approach starts with lifestyle modifications (exercise, diet, weight loss) first.
• If insufficient, metformin is commonly added, followed by a sulfonylurea, if needed.
• Other agents (acarbose, thiazolidinediones) are added later.

Summary of Pharmacological Targets and Actions of Drugs Used in the Treatment of DM

• Insulin and its analogues target the insulin receptor.
• Other agents are categorized by increasing or decreasing insulin release or enhancing its action.

Gila Monster

• The Gila monster (Heloderma suspectum) has provided insights into digestive processes, potentially leading to new treatments, despite its unusual eating patterns.

GLP-1 Modulates Numerous Functions in Humans

• GLP-1 secretion is triggered by food intake.
• Its functions include promoting satiety and reducing appetite, enhancing glucose-dependent insulin secretion, and helping regulate gastric emptying among other roles.

Release and Action of Glucagon-Like Peptide-1 (GLP-1)

• GLP-1 has a short half-life (less than 2 minutes) and is rapidly inactivated; this is what needs to be addressed for therapeutic purposes.
• Various forms of GLP-1 that resist this rapid breakdown (resulting in a longer duration) have been developed for diabetes or obesity treatment.

Types of Insulin Available (continued)

• Specific aspects of various insulin types (regular, NPH, lente, glargine, etc.) and their properties are provided.

Adverse effects of GLP-1 agonists and DPP-4 inhibitors

• Adverse effects of different classes of diabetes drugs are summarized.

SGLT2 Inhibitors

• SGLT2 inhibitors increase glucose excretion in urine.
• They help reduce blood glucose, improve weight, and benefit cardiovascular health, reducing hospitalization risks.
• Side effects: increased incidence in urinary tract or genital infections.

Adverse Reactions of Canagliflozin

• Increased risk of genital and urinary tract infections.
• Elevated risk of hypoglycemia.

Considerations Prior to Use of SGLT2 Inhibitors

• Potential acute kidney injury risk depends on factors such as reduced blood volume, congestive heart failure, and chronic kidney disease.
• Prior assessment and ongoing monitoring of kidney function are recommended.

Dapagliflozin (Farxiga®)

• Approved treatment for heart failure.
• May slow the progression of chronic kidney disease.

Primary Composite Outcome in Heart Failure Trials

• SGLT2 inhibitors effectively reduce the risk of cardiovascular death/hospitalization/urgent HF visit.

Farxiga (Dapagliflozin) Indications

• Improves glycemic control as an adjunct to diet and exercise.
• Reduces risk of heart failure-related hospitalization.
• Improves heart failure in adults with either type 2 diabetes or established cardiovascular disease.

2022 AHA/ACC/HFSA HF Guideline Updates

• These updated guidelines encompass several different stages of heart failure and highlight appropriate treatments for each stage.

The Need for Speed in Treatment

• A rapid, phased approach to initiating medications (with early introduction of SGLT2 inhibitors) is now advised for patients with heart failure and concurrent type 2 diabetes.

Diabetic Retinopathy

• Diabetic retinopathy results from leaky blood vessels in the retina, causing swelling (macular edema) and vision loss.

Diabetic Nephropathy

• Diabetic nephropathy characterized by changes in kidney structure and function.

Diabetic Neuropathy

• Diabetic neuropathy develops from damage to nerves, resulting in various symptoms like tingling, pain, and numbness in different parts of the body.

Diabetic Foot Ulcers

• Diabetic foot ulcers are open wounds on the feet.
• A combination of factors (artery disease, neuropathy, risk of infection) lead to ulcer development and delayed healing.

Diabetic Gangrene

• This is a severe form of tissue death, an advanced stage of diabetic complications.

Oral Pancreatic Enzymes (Pancrelipase)

• These enzymes (lipase, protease, and amylase) aid in fat, protein, and carbohydrate digestion.
• They are used to treat conditions in which pancreatic enzyme production is compromised (e.g., cystic fibrosis, surgical removal of the pancreas).
• Specific product (e.g., Creon) is mentioned.

Foot Care for Patients with Diabetes

• A detailed description of patient foot care recommendations are provided.