Endocrine Functions of the Pancreas

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Questions and Answers

What percentage of the pancreatic islets is made up of beta cells?

  • 10%
  • 80%
  • 70% (correct)
  • 20%

Which hormone is primarily responsible for lowering blood glucose levels?

  • Glucagon
  • Somatostatin
  • Insulin (correct)
  • Pancreatic polypeptide

In what part of the pancreas do endocrine cells primarily secrete hormones?

  • Into a duct
  • Near a capillary (correct)
  • Into the stomach
  • Into acini

What role do glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play in blood glucose regulation?

<p>They increase insulin release during meals. (C)</p> Signup and view all the answers

What is the primary function of the alpha cells in the pancreatic islets?

<p>To produce glucagon (D)</p> Signup and view all the answers

Which of the following best describes the lifespan of insulin in circulation?

<p>6 minutes (B)</p> Signup and view all the answers

Which cell type in the pancreatic islets produces somatostatin?

<p>Delta cells (A)</p> Signup and view all the answers

What is the role of ATP-sensitive potassium (KATP) channels in beta cells?

<p>They close due to increased ATP levels. (A)</p> Signup and view all the answers

What is the primary action of metformin?

<p>Inhibit hepatic glucose output (C)</p> Signup and view all the answers

What is a common side effect of thiazolidinediones (TZDs) like pioglitazone?

<p>Fluid retention (D)</p> Signup and view all the answers

Which class of diabetes medications primarily reduces postprandial hyperglycaemia by inhibiting α-glucosidase enzymes?

<p>Starch blockers (A)</p> Signup and view all the answers

What is a notable characteristic of repaglinide compared to sulphonylureas?

<p>Faster onset and offset kinetics (D)</p> Signup and view all the answers

Which of the following statements about insulin sensitizers is true?

<p>They reduce insulin resistance in peripheral tissues. (B)</p> Signup and view all the answers

Which side effect is most commonly associated with metformin?

<p>Lactic acidosis (A)</p> Signup and view all the answers

What effect do gliptins have on incretin levels?

<p>They raise levels of GLP-1. (C)</p> Signup and view all the answers

What does the term 'mellitus' refer to?

<p>Sweetness of urine (D)</p> Signup and view all the answers

Which symptom is not commonly associated with diabetes mellitus?

<p>Nausea (A)</p> Signup and view all the answers

Which type of diabetes mellitus typically has a sudden onset?

<p>Type 1 (C)</p> Signup and view all the answers

What is a common cause of Type 2 diabetes mellitus?

<p>Excess growth hormone (A)</p> Signup and view all the answers

What is a significant diagnostic criterion for diabetes?

<p>Fasting plasma glucose ≥ 7 mM (A)</p> Signup and view all the answers

Which of the following symptoms is especially prevalent in uncontrolled Type 1 diabetes mellitus?

<p>Ketosis (A)</p> Signup and view all the answers

At what age is Type 2 diabetes mellitus most commonly diagnosed?

<p>Over 40 years (C)</p> Signup and view all the answers

Which of the following can cause insulin resistance in Type 2 diabetes?

<p>Obesity (A)</p> Signup and view all the answers

What is one of the main distinguishing features of Type 1 diabetes mellitus?

<p>Absolute lack of insulin (B)</p> Signup and view all the answers

Which of the following is not a symptom of diabetes mellitus?

<p>Weight gain (A)</p> Signup and view all the answers

What type of hormone is insulin classified as?

<p>Anabolic hormone (D)</p> Signup and view all the answers

Which of the following statements about glucagon is correct?

<p>It increases gluconeogenesis in the liver. (D)</p> Signup and view all the answers

What triggers the release of insulin into the bloodstream?

<p>High blood glucose levels (A)</p> Signup and view all the answers

What is the role of amylin in the body?

<p>Slows gastric emptying (C)</p> Signup and view all the answers

Which glucose transporter is primarily influenced by insulin?

<p>GLUT4 (A)</p> Signup and view all the answers

Where is proinsulin converted into insulin?

<p>Golgi apparatus (B)</p> Signup and view all the answers

What is one of the main actions of glucagon?

<p>Increase glycogen breakdown (C)</p> Signup and view all the answers

What happens when blood glucose levels are low?

<p>Glucagon release is stimulated (B)</p> Signup and view all the answers

Which statement accurately describes the structure of insulin?

<p>It has two chains: an A chain of 21 amino acids and a B chain of 30 amino acids. (C)</p> Signup and view all the answers

How is diabetes mellitus primarily treated?

<p>Through dietary changes and insulin or hypoglycemic drugs (A)</p> Signup and view all the answers

Which of the following is a glucagon-like peptide 1 (GLP-1) agonist?

<p>Exenatide (A)</p> Signup and view all the answers

What is the primary mechanism of action for sulfonylureas?

<p>Stimulate insulin release from islet β cells (D)</p> Signup and view all the answers

What is the main reason for combining basal and prandial insulin in therapy?

<p>To achieve constant background insulin and manage mealtime spikes (A)</p> Signup and view all the answers

Which medication is classified as a biguanide?

<p>Metformin (C)</p> Signup and view all the answers

What distinguishes thiazolidinediones (TZDs) from other insulin sensitisers?

<p>They primarily act on peripheral tissues to enhance insulin sensitivity. (D)</p> Signup and view all the answers

What is the main side effect associated with sulfonylureas?

<p>Hypoglycemia (C)</p> Signup and view all the answers

What type of insulin is considered a prandial bolus preparation?

<p>Lispro (A)</p> Signup and view all the answers

Which of the following is NOT a main effect of insulin secretagogues?

<p>Reducing insulin sensitivity (B)</p> Signup and view all the answers

What type of insulin is Neutral Protamine Hagedorn (NPH)?

<p>Intermediate-acting (B)</p> Signup and view all the answers

What aspect of insulin therapy must be personalized and adjusted for each patient?

<p>Insulin regimen based on activity, meals, and blood glucose levels (A)</p> Signup and view all the answers

Flashcards

Pancreas

A flattened organ located posterior and slightly inferior to the stomach, classified as both an endocrine and an exocrine gland.

Acinar cells

Clusters of cells in the pancreas that produce digestive enzymes.

Pancreatic islets (Islets of Langerhans)

Specialized groups of cells within the pancreas responsible for producing hormones.

Glucagon

A hormone produced by alpha cells in the pancreatic islets, responsible for raising blood glucose levels.

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Insulin

A hormone produced by beta cells in the pancreatic islets, responsible for lowering blood glucose levels. It facilitates glucose uptake by cells for energy.

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Regulation of Blood Glucose

The process by which insulin, glucagon, and other hormones maintain blood glucose levels within a healthy range.

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Incretin effect

A group of hormones, including GLP-1 and GIP, released from the gastrointestinal tract, that stimulate insulin secretion after meals.

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Amylin

A peptide hormone produced by beta cells alongside insulin, that plays a role in regulating blood glucose by inhibiting hepatic gluconeogenesis.

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Glycolysis

The process of breaking down glucose for energy production. It is stimulated by insulin.

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Diabetes Mellitus

A condition characterized by high blood sugar levels due to either insufficient insulin production (Type 1) or insulin resistance (Type 2).

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Gluconeogenesis

The process of creating new glucose molecules from non-carbohydrate sources, such as amino acids or glycerol. It is stimulated by glucagon.

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Glycogen Synthesis

The process of storing glucose in the liver and muscle as glycogen. It is stimulated by insulin.

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Glycogenolysis

The breakdown of stored glycogen into glucose. It is stimulated by glucagon.

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Beta Cells

Specialized cells within the pancreas that produce insulin.

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Alpha Cells

Specialized cells within the pancreas that produce glucagon.

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Ketoacidosis

A life-threatening condition where the body produces excessive amounts of ketones, leading to a buildup of acid in the blood.

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Hyperglycemia

A condition where the blood glucose level is elevated.

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Glycosuria

A condition where sugar is present in the urine.

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Polydipsia

Increased thirst.

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Polyuria

Increased urination.

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Polyphagia

Increased hunger.

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Type 1 Diabetes

The autoimmune destruction of beta cells in the pancreas, leading to insufficient insulin production.

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Type 2 Diabetes

Insulin resistance develops, leading to decreased insulin sensitivity and eventually insufficient insulin production by the pancreas.

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HbA1c

A blood test that measures average blood sugar control over the past 2-3 months.

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Thiazolidinediones (TZDs)/Glitazones

A class of drugs that enhance insulin sensitivity by activating a specific nuclear receptor called PPAR-gamma. This action primarily occurs in muscle tissue, reducing peripheral insulin resistance.

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Gliptins

A drug that inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), which normally breaks down incretin hormones like GLP-1. This leads to increased levels of GLP-1, promoting insulin secretion and reducing blood glucose.

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Starch Blockers

A class of drugs that block the breakdown of starch and sucrose in the gut by inhibiting the enzyme alpha-glucosidase. This slows down the absorption of glucose from the gut, reducing postprandial hyperglycemia.

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Metformin (Biguanide)

A drug that primarily acts in the liver, reducing glucose production (glycogenolysis and gluconeogenesis) and enhancing insulin sensitivity. It also decreases glucose absorption from the gut.

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Repaglinide

A medication that enhances insulin secretion by selectively stimulating beta cells in the pancreas. It works by targeting the ATP-sensitive potassium channels (KATP) in beta cells.

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Insulin Secretagogues

Drugs that stimulate the pancreas to release insulin, regardless of blood glucose levels.

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Sulfonylureas

A class of insulin secretagogues that bind to a specific protein on pancreatic cells, blocking a channel and causing insulin release.

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Insulin Sensitizer

A medication that enhances insulin sensitivity in tissues, improving glucose uptake.

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Thiazolidinediones (TZDs)

A type of oral medication that increases insulin sensitivity by acting on a specific protein receptor in the body.

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Meglitinides (Glinides)

A type of medication used to treat type 2 diabetes that stimulate insulin release from the pancreas.

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Glucagon-Like Peptide 1 (GLP-1)

A hormone secreted in the gut that plays a role in regulating blood sugar levels.

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GLP-1 Agonists

A type of medication designed to mimic the action of GLP-1, enhancing insulin release and slowing down glucose absorption.

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DPP-4 Inhibitors

A medication that blocks an enzyme called DPP-4, which breaks down GLP-1, thereby increasing GLP-1 levels in the body.

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Biguanides

A class of medications that act primarily by suppressing production of glucose from the liver.

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Basal Insulin

Insulin preparations designed to provide a steady, long-lasting effect on blood glucose levels.

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Study Notes

The Endocrine Pancreas, Diabetes Mellitus & Pharmacotherapeutics

  • The pancreas is a flattened organ located posterior and slightly inferior to the stomach
  • It is classified as both an endocrine and exocrine gland
  • Histologically, it consists of pancreatic islets (or islets of Langerhans) and clusters of cells (acini) which produce digestive enzymes (exocrine cells)
  • The pancreas is 5 inches long and consists of head, body, and tail
  • 99% of the cells in acini produce digestive enzymes
  • Endocrine cells in pancreatic islets produce hormones

Pancreatic Islets (Islets of Langerhans)

  • There are 1 to 2 million pancreatic islets per human pancreas (approximately 1-2% of the pancreas' weight)
  • Contains 4 types of endocrine cells

Cell Types in Pancreatic Islets

  • Alpha cells (20%) produce glucagon
  • Beta cells (70%) produce insulin and amylin
  • Delta cells (5%) produce somatostatin
  • PP cells produce pancreatic polypeptide
  • Human pancreas contains 8 mg of insulin; secretes 0.5 to 1 mg per day
  • Insulin is rapidly destroyed by liver & kidney (half-life in circulation is about 6 minutes)

Regulation of Blood Glucose

  • When blood glucose increases, the pancreas secretes insulin to bring glucose levels back to normal
  • Glucose enters beta cells via GLUT2 glucose transporter
  • ATP synthesis increases
  • ATP-sensitive potassium (KATP) channels close
  • Insulin is released and reduces blood glucose levels
  • When blood glucose is low, the pancreas secretes glucagon to maintain stable levels
  • Glucagon increases blood glucose levels
  • Insulin and glucagon have opposing actions

Primary Targets for Insulin Action

  • Liver
  • Skeletal muscle
  • Adipose tissue
  • Pancreatic alpha cells (to inhibit glucagon release)
  • Note: Skeletal muscle and fat depend on insulin for glucose uptake

Insulin Promoting + Counter-Regulatory Hormones

  • Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) increase prandial insulin release ("incretin" effect) from the GI tract
  • Amylin inhibits hepatic gluconeogenesis
  • Glucagon, catecholamines (e.g., noradrenaline, adrenaline), glucocorticoids (e.g., cortisol), and growth hormone oppose insulin action

Regulation of Blood Glucose (Detailed)

  • Low blood glucose stimulates alpha cells to release glucagon
  • Glucagon acts on hepatocytes to form glucose from glycogen (glycogenolysis) or from lactic acid and amino acids (gluconeogenesis); this raises blood glucose levels to normal
  • If blood glucose continues to rise, hyperglycemia inhibits the release of glucagon
  • High blood glucose stimulates beta cells to release insulin
  • Insulin acts on various body cells to accelerate glucose diffusion, speed glucose conversion to glycogen (glycogenesis), increase amino acid and protein synthesis, and slow glycogenolysis and gluconeogenesis
  • If blood glucose continues to fall, hypoglycemia inhibits the release of insulin

Insulin

  • Isolated in 1921 by Banting and Best
  • Sequenced in 1955 by Sanger
  • Gene on chromosome 11 in humans
  • Human gene isolated and used to make human insulin from bacteria
  • Insulin contains 2 chains (A chain 21 amino acids and B chain 30 amino acids). Only one amino acid differs between pig and human insulin.

Structure of Bovine Insulin

  • Detailed structure with amino acid sequences for A and B chains

Synthesis of Insulin

  • Insulin is synthesized in the RER of beta islet cells as preproinsulin
  • 23 amino acids are removed to form proinsulin in RER
  • In Golgi apparatus, proinsulin is packaged into vesicles where it is cleaved into insulin & C peptide
  • Released by exocytosis when high blood sugar is present in the blood

Insulin Actions

  • Stimulates uptake of glucose in insulin-sensitive tissues, like skeletal muscle and fat (via GLUT4 glucose transporter)
  • Stimulates glycogen synthesis
  • Stimulates lipid synthesis
  • Stimulates protein synthesis
  • Stimulates DNA/RNA synthesis
  • Stimulates glycolysis

Amylin

  • A 37 amino acid protein
  • Co-released with insulin
  • Actions in the CNS, inhibiting glucagon release; slows gastric emptying; decreases food intake
  • Cleared by kidneys (half-life of approximately 10 minutes)

Glucagon

  • Fasting hormone & hormone of energy release (catabolic)
  • Secreted by alpha islet cells
  • A 29 amino acid linear polypeptide synthesized as preproglucagon and degraded by the liver and kidneys (half-life approximately 6 minutes)
  • Primarily acts on the liver to increase glycogen breakdown, lipolysis, ketone body formation, and gluconeogenesis

Insulin Actions (Synthesis/Breakdown Summary Table)

  • Table summarizing the effects of insulin on synthesis and breakdown of protein, lipids, glycogen, DNA/RNA, glucose (gluconeogenesis) and glycolysis, and on the liver.

Glucose Transporters

  • Table listing glucose transporter types, their tissue expression, and their role.

Glucose Transport Mechanism

  • Detailed explanation of glucose transport, including the roles of vesicles and insulin receptors, with diagrams.

Pancreas Summary

  • The endocrine pancreas mainly produces insulin and glucagon
  • Insulin and glucagon control blood glucose levels
  • Lack of insulin results in diabetes mellitus
  • Diabetes mellitus can be divided into Type 1 and Type 2
  • Diabetes mellitus can be treated with diet, exogenous insulin, and various hypoglycemic drugs in Type 2 DM.

Diabetes: Two Diseases

  • Diabetes insipidus (posterior pituitary disease)
  • Diabetes mellitus (pancreas disease)
  • Diabetes mellitus was first described by the Egyptians in 550 BC
  • "Diabetes" means "pass through" in Greek, referring to the excessive urination
  • "Mellitus" meaning "honey sweet" was added to the name in 1700s

Two Major Types of Diabetes Mellitus

  • Type 1
  • Type 2

Diabetes Mellitus Signs and Symptoms

  • Main signs and symptoms of diabetes, including:
    • Polyuria
    • Polydipsia
    • Polyphagia
    • Hyperglycemia
    • Glycosuria
    • Ketosis
    • Acidosis
    • Rapid weight loss
    • Weakness, drowsiness, and fatigue
    • Skin problems
    • Visual problems
    • Coma

Criteria for Diagnosing Diabetes

  • Diabetes symptoms plus a random venous glucose concentration ≥ 11.1 mM or a fasting plasma glucose ≥ 7mM or a 2-hour plasma glucose concentration ≥11.1 mM 2 hours after a 75g glucose tolerance test (OGTT).
  • An HbA1c of 48mmol/mol (6.5%) may be used for diagnosis.

Causes of Diabetes Mellitus

  • Autoimmune destruction of beta cells (Type 1 DM)
  • Excess insulin antagonists (e.g., growth hormone)
  • Insulin receptor problems/insulin resistance (Type 2 DM)
  • Defective insulin release (Type 2 DM)
  • Abnormal insulin produced
  • Drug or chemical damage
  • Pancreatitis
  • Problems with glucose transport.

Types of Diabetes Mellitus (Detailed Comparison)

  • Table comparing Type 1 and Type 2 diabetes based on onset, type of onset, obesity, symptoms, ketosis, endogenous insulin, islet cells, insulin therapy, hypoglycemic drugs, diet, family history, HLA-associated, seasonal trends, possible causes, vascular problems, sex ratio.

Diabetes Mellitus: Acute Complications

  • Diabetic ketoacidosis (particularly uncontrolled Type 1 DM)
  • Hyperglycemia
  • Hyperosmolar Hyperglycemic State (HHS) (associated with Type 2 DM)
  • Iatrogenic hypoglycemia

Diabetes Mellitus: Chronic Complications

  • Retinopathy (eye problems)
  • Neuropathy (nerve damage)
  • Nephropathy (kidney problems)
  • Heart attack & stroke (atherothrombotic problems)
  • Diabetic foot (circulatory problems)
  • Gum disease (infection & circulatory problems)
  • Increased cancer risk (tumorigenesis problems)
  • Sexual dysfunction (nervous & circulatory problems)

Diabetes Mellitus Therapy

  • Type 1 DM: exogenous insulin + diet control
  • Type 2 DM:
    • Dietary therapy (especially if overweight)
    • Drug therapy + diet control
    • Exogenous insulin + diet control

Pharmacotherapeutics of Anti-Diabetic Agents

  • Exogenous insulin preparations (e.g., regular insulin, insulin lispro, insulin glargine)
  • Inhibitors of glucose absorption ("starch blockers") (e.g., acarbose)
  • Enhancers of glucose excretion (e.g., dapagliflozin)
  • Insulin secretagogues (e.g., tolbutamide, glipizide, repaglinide)
  • Glucagon-like peptide-1 (GLP-1), "incretin"-based therapy (e.g., exenatide, liraglutide)
  • Insulin sensitizers (e.g., pioglitazone, metformin)
  • Starch blockers (e.g., acarbose)

Common Insulin Preparations

  • Prandial bolus (short/rapid acting): regular, lispro, aspart, glulisine
  • Basal (intermediate/long acting): neutral protamine hagedorn (NPH), glargine, detemir

Insulin Therapy

  • Indicated in Type 1 DM + Type 2 DM insufficiently responsive to diet and oral hypoglycaemic agents
  • Administered by subcutaneous injection
  • Typically, basal preparation (constant low-level background insulin) + prandial bolus preparations (before meals)
  • Personalised regimen (e.g., preparation, dosage, frequency) , adjusted to patient's activity, meals, and blood glucose

Sulphonylureas

  • Insulin secretagogues; stimulate islet B cells to release insulin (in a glucose independent manner) e.g., tolbutamide, glipizide, glimepiride
  • Bind to SUR1 subunit on ATP-dependent potassium (KATP) channel leading to channel blockade, depolarization then insulin release
  • Side effects include hypoglycaemia, weight gain, and digestive problems

Meglitinides (Glinides)

  • Insulin secretagogues e.g., repaglinide
  • Similar action site & mechanism to sulphonylureas but more selective for beta-cell KATP channels
  • Rapid onset & offset; short-duration action
  • Less potent than sulphonylureas; reduce postprandial hyperglycaemia; typically administered before meals
  • Side effects similar to sulphonylureas but lower risk of hypoglycaemia and weight gain

Biguanides

  • Insulin sensitiser (e.g., Metformin)
  • Inhibits hepatic glucose output (predominantly in liver); inhibits glucose absorption from gut
  • Activates hepatic adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)
  • Increases insulin receptor activity; reduces insulin resistance
  • Enhances insulin effects in target tissues; increases insulin-dependent glucose uptake by muscle and fat
  • Low risk of hypoglycaemia (as monotherapy), no weight gain (some weight loss possible)
  • Side effects include gastrointestinal upset, altered taste, decreased appetite, vitamin B12 deficiency, and lactic acidosis

Starch Blockers

  • Inhibit a-glucosidase enzymes in the gut; block starch and sucrose breakdown; reduce/delay glucose absorption from the gut e.g., acarbose
  • Few side effects; no weight gain
  • Low/no risk of hypoglycaemia (as monotherapy)
  • Reduces postprandial hyperglycaemia
  • Common side effects: GI upset, flatulence, aminotransferase elevation, raised triglycerides

Thiazolidinediones (TZDs)/Glitazones

  • Insulin sensitiser (e.g., Pioglitazone)
  • Stimulates nuclear hormone receptor PPAR-γ; predominant action in muscle
  • Reduces peripheral insulin resistance; reduces insulin levels, triglycerides, and free fatty acids
  • Side effects: weight gain, fluid retention, oedema, anaemia, gastrointestinal upset, headache, fatigue, potential liver toxicity (monitor), and possible increased LDL cholesterol

GLP-1 agonists

  • Analogues of GLP-1 (DPP-4 resistant)
  • Mimic actions of GLP-1 e.g., exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, tirzepatide
  • Enhances glucose-dependent insulin release; decrease glucagon release; increase hepatic glucose production and delay gastric emptying
  • Appetite suppression; weight loss
  • Side effects: gastrointestinal disturbances, gastroesophageal reflux disease, hypoglycemia, headache, and dizziness

Glinides

  • Sodium glucose-linked transporter-2 (SGLT-2) inhibitors; e.g., dapagliflozin, canagliflozin, empagliflozin, ertugliflozin
  • Prevent proximal tubular reabsorption of filtered glucose from the renal filtrate
  • Low risk of hypoglycemia; weight loss
  • Side effects include polyuria, dehydration, aggravated glycosuria, genital and urinary tract infections, skin infections, increased risk of diabetic ketoacidosis

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