Insulin Functions in the Liver

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Questions and Answers

What is one of the primary actions of insulin in the liver?

Promotes ketogenesis

Increases glycogen synthesis (correct)

Stimulates amino acid transport

Inhibits glucose uptake

What characterizes Type 1 Diabetes Mellitus?

Progressive muscle resistance to insulin

Autoimmune destruction of pancreatic beta cells (correct)

Does not require insulin therapy

Higher prevalence in adults

What is a common symptom of diabetes mellitus?

Increased sensitivity to cold

Frequent urination (correct)

Excessive hair growth

Rapid weight gain

How does insulin affect adipose tissue?

Stimulates glucose uptake Signup and view all the answers

What typically describes the insulin levels in Type 2 Diabetes Mellitus?

Decreased responsiveness of peripheral tissues to insulin Signup and view all the answers

Which of the following drugs is likely to cause hypoglycemia?

Salicylates Signup and view all the answers

What is a common characteristic of symptoms experienced by individuals with diabetes?

Extreme fatigue Signup and view all the answers

Which of the following best describes the etiology of diabetes mellitus?

Increase in insulin resistance and/or decrease in insulin production Signup and view all the answers

What is the peak time for Regular insulin?

1.5-4h Signup and view all the answers

Which insulin preparation has an onset time of 2-5 hours?

Glargine Signup and view all the answers

What percentage of the daily dose is typically allocated for short-acting insulin in a typical BD regimen?

30% Signup and view all the answers

Who is intensive treatment typically indicated for?

Type I and motivated patients Signup and view all the answers

What is a significant risk associated with intensive insulin regimens?

Increased hypoglycemia risk Signup and view all the answers

What is the usual duration of action for NPH insulin?

18-24 hours Signup and view all the answers

Which combination of insulins is commonly associated with premixed formulations?

75% NPH + 25% Regular Signup and view all the answers

What is a common use for IV infusion of regular insulin?

For ketoacidosis Signup and view all the answers

What is the maximum recommended dose of repaglinide per day?

8 mg Signup and view all the answers

Which of the following is a common adverse effect associated with glinides?

Weight gain Signup and view all the answers

How do glinides primarily function to manage glucose levels?

Stimulate rapid but short-lived insulin release Signup and view all the answers

In which condition should glinides be used with caution?

Hepatic impairment Signup and view all the answers

What has become the standard form of insulin therapy in the last decade?

Human insulin Signup and view all the answers

What is the primary mechanism of thiazolidinediones?

Increase insulin sensitivity in target tissues Signup and view all the answers

Which side effect is NOT commonly associated with thiazolidinediones?

Hyperglycemia Signup and view all the answers

What primarily causes hypoglycemia in patients undergoing insulin therapy?

Overdose or failure to eat Signup and view all the answers

What effect do alpha-glucosidase inhibitors have on carbohydrate absorption?

Reduce intestinal absorption of carbohydrates Signup and view all the answers

In adult Type 1 diabetes, what is a typical starting insulin dose per kg of lean body mass?

0.5 units/kg Signup and view all the answers

What is a primary action of glucagon in emergency hypoglycemia treatment?

Convert stored glycogen into glucose Signup and view all the answers

What side effect is commonly reported with alpha-glucosidase inhibitors?

Flatulence Signup and view all the answers

Which of the following properties is true for Metformin?

Reduced hepatic gluconeogenesis Signup and view all the answers

Which group of oral anti-diabetic drugs works by increasing insulin secretion?

SULFONYLUREAS Signup and view all the answers

What is the primary action of sulfonylureas in diabetes treatment?

Stimulate insulin secretion Signup and view all the answers

What is the starting recommended dose of glimepiride for those at risk of hypoglycemia?

1 mg daily Signup and view all the answers

Which drug reduces hepatic glucose output by targeting glucagon secretion?

GLP-1 Signup and view all the answers

How do thiazolidinediones primarily exert their effects?

Targeting PPARγ to increase insulin sensitivity Signup and view all the answers

What is a common side effect of Metformin?

Gastrointestinal effects Signup and view all the answers

What common intervention is often reviewed after three months if initial treatment fails?

Compliance with the treatment plan Signup and view all the answers

What physiological function does GLP-1 promote after food ingestion?

Promotes satiety and reduces appetite Signup and view all the answers

Which agent targets α-glucosidases to reduce carbohydrate absorption?

Acarbose Signup and view all the answers

What role does insulin play in glucose metabolism?

Promotes glucose uptake in muscle and fat tissues Signup and view all the answers

What is a potential consequence of insulin deficiency in diabetes management?

Increased hepatic glucose output Signup and view all the answers

What is the half-life of GLP-1 in its active form?

10 minutes Signup and view all the answers

Which of the following GLP-1 receptor agonists is administered once weekly?

Dulaglutide (Trulicity®) Signup and view all the answers

Which GLP-1 treatment has been approved to reduce the risk of cardiovascular death?

Semaglutide Signup and view all the answers

What is the main action of GLP-1 in the body?

Stimulating insulin secretion Signup and view all the answers

Which of the following statements about oral GLP-1 treatments is correct?

Rybelsus® is indicated to improve blood sugar control in type 2 diabetes. Signup and view all the answers

What is the specific mechanism of action for DPP-4 inhibitors?

Inhibiting GLP-1 degradation Signup and view all the answers

Which of the following has NOT been mentioned as an approved use for liraglutide (Victoza®)?

Reducing risk of heart attack Signup and view all the answers

What was the approximate sales figure for obesity treatments in 2023?

$4.6 billion Signup and view all the answers

Study Notes

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.

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Description

This quiz explores the primary actions of insulin in the liver, focusing on its role in glucose metabolism and storage. Test your knowledge on how insulin impacts liver function and the metabolic processes involved.