Glucose Homeostasis and Diabetes

• Glucose homeostasis and diabetes is the topic. The lectures were presented by Dr. Gruber on March 5th, 2025.

Learning Objectives

• Understand the mechanisms underlying glucose control.
• Understand the regulation of blood glucose by the endocrine pancreas.
• Understand the importance of counter-regulatory mechanisms.
• Understand the major types of diabetes, their pathophysiology, and treatment rationale.
• Understand the similarities and differences in pathophysiology and why we need to adjust treatment strategies
• Using insulin sensitizers alone is insufficient for type 1 diabetes (T1D).
• Understand the rationale for and mechanisms of action of drugs used in the treatment of diabetes.

Central Tenants of Glucose Homeostasis

• Glucose must be sensed to maintain glucose control.
• Sensing must be translated to a physiological response
• The need to respond to increases and decreases in blood glucose is crucial.

Glucose Homeostasis Elements

• Glucose levels are tightly regulated by various hormones and mechanisms.
• Regulation includes feedback from the gut and information from the CNS.
• The hormones insulin and glucagon play opposing regulatory roles.
• Insulin levels rise when blood glucose or nutrient levels are high, promoting glucose uptake and nutrient storage as part of the "rest and digest" process.
• Glucagon levels increase when blood glucose is low, which stimulates endogenous glucose production, lipolysis, and ketogenesis in a "fight or flight" response.

Fasting Conditions Necessities

• During fasting, there is low serum glucose
• Fuel demands are met by oxidizing fatty acids, except in the CNS. The CNS must use glucose as an energy source though it can also use ketones.
• Breakdown of liver glycogen stores (glycogenolysis) and conversion of lactate into glucose (hepatic gluconeogenesis) provide glucose during fasting.
• The processes are regulated by insulin and glucagon.
• Insulin relieves the inhibition of gluconeogenesis; thus, the drop in insulin during fasting aids glucose output.
• Increased Glucagon stimulates gluconeogenesis and hepatic glycogenolysis to maintain blood glucose during fasting.
• Plasma insulin is low and glucagon is high to promote hepatic glycogenolysis and gluconeogenesis.
• Low insulin levels cause increased lipolysis in adipose tissue.
• Free fatty acids released during lipolysis are used for energy through oxidation.
• The liver converts fatty acids into ketones for use by the brain.

Fed Conditions Info

• Fed/postprandial state involves high serum glucose.
• Energy is readily available, eliminating the need to breakdown long-term energy stores or produce endogenous glucose.
• Increased insulin leads to glucose-stimulated insulin secretion, which results in increased lipogenesis, glycogen production, and glucose uptake from the circulation.
• Decreased glucagon inhibits secretion of glucagon.
• Low glucagon levels mean reduced glucagon signaling to peripheral tissues and reduced glucagon-mediated lipolysis, glycogenolysis, and gluconeogenesis.
• Glucagon can "fine-tune" insulin secretion in a paracrine manner through "intra-islet" signaling.
• Glucagon can boost insulin secretion under high glucose conditions.
• Increased plasma glucose from nutrient absorption causes cells to release gut incretins (GLP-I) and insulin from the pancreas.
• Insulin increases glucose uptake by the liver, skeletal muscle, and adipose tissue.
• Insulin also inhibits hepatic glucose production and lipolysis, promoting glycogen synthesis.
• Brain provides regulatory inputs to maintain fuel homeostasis.

Pancreatic Hormones

• Islets of Langerhans are where different hormones are manufactured and secreted:
• Beta cells produce Insulin, which makes up ~50% of islet cells.
• Alpha cells produce Glucagon, which accounts for 20-30% of islet cells, this increases insulin secretion under high glucose conditions.
• Delta cells produce Somatostatin, at ~5% of cells and inhibits release of insulin and glucagon.
• Entero-endocrine hormones like GLP-1 from the gut enhances insulin release.

Insulin Release

• Glucose enters pancreatic beta cells via GLUT2 transporters
• Glucose gets metabolized by glucokinase and glycolysis
• This increases the ATP which reduces ADP, raising the ATP/ADP ratio.
• Increased ATP inhibits KATP channels, causing membrane depolarization.
• Depolarization opens voltage-gated calcium channels (VGCC),leading to Ca2+ influx.
• Increased intracellular Ca2+ triggers insulin exocytosis.
• Insulin release is graded, so it responds to the blood glucose levels.
• Incretins from the gut amplify this process.

Aspects of Insulin Secretion

• First-phase involves the immediate release of stored insulin upon initial glucose sensing, peaking within 2 minutes and ending by 10 minutes.
• Prevents rapid glucose spikes after eating, and counters the effects of glucagon while fasting
• Second-phase consists of a slower release that sustains insulin secretion to maintain glycemia over a longer time.
• It is crucial for peripheral glucose uptake and clearance.
• Deficits in FPIS can be an early indicator of metabolic problems but are tough to measure clinically
• SPIS impairment can impair glucose clearance.
• Insulin release is biphasic; with first phase impairment in T2DM, and both phases absent in T1DM

Insulin Receptor Info

• Tyrosine kinase-linked receptor has 2 alpha and 2 beta sub-units.
• Alpha sub-units bind to insulin while beta is catalytic.
• Insulin binding results in receptor dimerization and auto-phosphorylation on tyrosine residues.
• This phosphorylation leads to a cascade effect through the insulin receptor substrate (IRS) proteins.
• IRS proteins interact with -SH2 domain-containing proteins, activating downstream kinases like the AKT pathway.

Insulin Actions

• Insulin is an anabolic hormone that facilitates the uptake and storage of glucose, amino acids, and fats. Additionally, insulin reduces catabolism.
• Liver: Inhibits glycogenolysis and gluconeogenesis but promotes glycogen synthesis and lipogenesis.
• Muscle: Increases glucose uptake via GLUT4 and stimulates glycogen synthesis.
• Adipose tissue: Boosts glucose uptake via GLUT4 and encourages glycerol and fatty acid synthesis.
• Increases glycogen and triglyceride stores
• Insulin supports energy storage through glycogen and lipids as part of a “rest and digest” response.

Insulin Secretion and Regulation

• Insulin secretagogues are agents that boost insulin secretion.
• They Include glucose, amino acids, fatty acids, parasympathetic stimulation, incretins, and sulphonylureas
• Insulin secretion inhibitors include somatostatin, low plasma glucose, and sympathetic stimulation.
• Incretins like glucagon-like peptide 1 (GLP-1) are released when food is ingested.
• GLP-1 stimulates insulin release, inhibits glucagon secretion, and is terminated by dipeptidyl peptidase-4 (DPP-4).
• Stimulation of first peak insulin release is due to GPCR which is couple to adenylyl cyclase - cAMP/Ca+ mediated exocytosis
• The effect of GLP-1 is glucose dependent and has a lower risk of hypoglycemia.

Glucose Control Regulation

• Hyperglycemia presents long-term harm, while hypoglycemia poses an immediate threat.
• Multiple counter-regulatory mechanisms counter hypoglycemia through:
• Brain initiates autonomic responses.
• The pancreas produces glucagon.
• Adrenal glands secretes cortisol and epinephrine.

Elements of Glucagon

• It's a peptide hormone produced in alpha cells (and in the GI)
• It mobilizes fuel by "fight or flight" response, while insulin handles the "rest and digest"
• Glucagon is stimulated by amino acids, low glucose levels , and sympathetic activation.
• Glucagon is suppressed by somatostatin, GLP-1 and high glucose levels.
• A-cells make up 40% of islet mass

Adrenergic Receptors Info

• Alpha 1-Adrenergic Receptors
• Cause vasoconstriction.
• Increases peripheral resistance and blood pressure.
• Induces mydriasis.
• Causes closure of bladder sphincters.
• Increases hypophagia.
• Alpha 2-Adrenergic Receptors
• Cause inhibition of norepinephrine and acetylcholine release.
• Inhibits insulin release.
• Promotes feeding.
• Increases glucagon release.
• Beta 1-Adrenergic Receptors
• Increases heart rate, lipolysis, and myocardial contractility.
• Increases renin secretion
• Beta 2-Adrenergic Receptors
• Cause vasodilation and bronchodilation.
• Decreases peripheral resistance.
• Increases glycogenolysis and glucagon release.
• Relaxes the uterine smooth muscle.

Glucagon Secretion and Action

• In the brain, it increases satiety and hepatic glucose output.
• Facilitates glycogenolysis, gluconeogenesis, glycogenesis, lipid oxidation, and lipid synthesis in the liver
• Stimulates the heart
• Influences water reabsorption in the Kidney, glomerular filtration and electrolyte excretion
• In Adipose Tissue, glucagon increase lipolysis and oxygen consumption
• Acts on Gut to modulate motility, gastric emptying

Glucagon Actions

• Glucagon increases plasma glucose and causes breakdown of fat and protein for use as energy
• In glycogenolysis and gluconeogenesis it increases and decreases respectively.
• In glycogen synthesis decreases
• In glucose oxidation it decreases
• In lipolysis it increases
• A "fight or flight" type hormone, triggered by catecholamines, it facilitates energy utilization, and liberates energy storage while digestion slows.
• It is used therapeutically for hypoglycemia. If patient unconscious (i.m., s.c. or i.v.) and T1D patients carry glucagon with them, but its expensive
• Glucagon receptors agonists are being tested in co-agonist incretin-based therapies for obesity

Diabetes Definition

• Diabetes is from a Greek word for polyuria
• Diabetes Mellitus means "lots of sweet urine"
• Is a spectrum of metabolic disorders involving reduced insulin secretion, reduced responsiveness to insulin, increased abnormal glucose production, and/or abnormalities in fat and protein metabolism.
• Included in the types are Type I (TIDM) and Type 2 (T2DM), and Gestational Diabetes (GDM)

Relevant Info on Diabetes Mellitus (DM)

• A chronic metabolic disorder characterized by high blood glucose levels
• Hyperglycemia is derived from increased gluconeogenesis and reduced uptake of glucose.
• The ability of insulin to regulate the process is Impaired.
• This can be due to insulin resistance, insufficiency, or both.
• The diagnostic criteria are fasting blood glucose levels >7mmol/L and HbA1c>6.5%.
• Glucose in urine causes osmotic diuresis with symptoms of dehydration, thirst and increased drinking and urination.
• This can contribute to weight loss seen in TID patients.
• Complications include cardiovascular disease, renal disease, birth complications and dementia

Types of Diabetes

• TIDM (Type 1)
• Represents ~10% of cases.
• Includes immune-mediated or idiopathic factors.
• There is destruction of beta cells in the pancreas
• T2DM (Type 2)
• Accounts for ~90% of cases.
• The body does not produce or respond correctly to insulin.
• Gestational Diabetes
• Is the insufficient insulin secretion and responsiveness during the pregnancy
• It is distinct from Type 2 Diabetes but can be lumped in with it often

Risk Factors for Diabetes

• T1D risk factors:
• Occurs in young adults (<25), teens and children.
• Having family history and environment is a concern. -There are strong genetic components that are related to certain genes.
• GDM risk factors:
• Advanced maternal age and a history of GDM pregnancy can be causes.
• Increased risk with subsequent pregnancy and family history is a concern.
• Have given birth to a large baby
• PCOS(Polycystic ovary syndrome)
• T2D is social, economical, and environmentally disrupted.
• Non-modifiable factors include Sex, Age, and Genetic Risk -> Modifiable risks includes Obesity, hypertension, and the environment.

Insulin Secretion in Diabetes

• During TIDM, the body may have progressive and immune-mediated loss of beta-cell function
• This is in conjunction with insulin secretions capacity.
• Resulting in hyperglycemia that appears in childhood, adolescence or young adulthood
• During T2DM, insulin resistance of peripheral tissues occurs during resistance.
• The result of this situation can impair the ability of insulin in the body.
• This may lead to compensation, beta cells fail, and hyperglycemia can proceed as unchecked.
• In T2DM, obesity is a cause resistance and will over nutrite the state.

Therapeutic Strategies to Improve Diabetes

• Help the areas identified in impairments
• Reduce the high risk of complications
• Provide a focus on impaired Glucose homeostasis.

Key Questions to Know and Understand

• Importance of glucoregulatory control and the consequences of dysregulation.
• What diabetes is, and how it is linked to impaired glucose control
• The mechanisms involved in the control & regulation of glucose levels.
• The functions of glucagon and insulin in fed/fasted states.
• How insulin and glucagon are secreted, and from what cells.
• What regulates secretion of glucagon and insulin and the tissue-specific effects.
• What is the incretin effect and how it impacts glucose regulation.
• What insulin resistance and the consequences of this.
• How can people with obesity impact insulin resistance.
• The process of resistance that leads to diabetes.

Managing Diabetes

• Diabetes Pharmacotherapies were presented on March 7, 2025, by Dr. Brittany Gruber
• Managing diabetes includes Glycemic control with Lifestyle and medication
• You can treat the condition with screen to manage complication. This include Retinopathy or cardiovascular
• If possible, the goal is to try to lower HbA1c: and affect with change

Signs and Symptoms of Diabetes

• Increased urination and Increased thirst/appetite
• Fatigue or Blurred Vision
• Weight change in unexplained manner (loss more common in T1D)
• Frequent infections or delayed wound healing

Tests Used to Diagnose Diabetes

• The fasting blood glucose that over 7-mmol/L can be sign. Random plasma glucose. Can also work
• HbA1c with a factor over 6.5% (can work in random plasma)
• Another considerations involve glucose test that will have to test on the test
• It is worth the assessment the auto-antibodies if it is a diabetes type test
• Also with genetic polymorphism

What are the Long Term Implications

• Includes blindness with stroke
• Renal and Kidney failure from damage nerve
• Hypoglycemia from the vascular or dementia vascular related

What are the Details on Type 1 Diabetes

• Known as (IDDM) for Juvenile Onset
• Only 5-10% of all the cases.
• It is a younger, typically genetic age set.

What is Glucagon?

• A peptide hormone produced in alpha cells, that Mobilzes fuel and fights or flight.
• Is increased with activity.

Clinical Goals for Treating Diabetes

• Regulate glucose to alleviat symptoms and avoid chornic complicatoins.
• Regular Glucose check monitoring that is controlled well in counting
• There is destruction of GL for oral intake
• It will have a fast response to take action.

Human and Insulin Replacement Details

• These methods of action can peak to make the impact
• It also can be sub-classified where can be created form biosimilars
• Many are will be used for those whom may need formulation

Insulin Replacement Properties

• For human, they can produce with plasmids. Then suspended to do in bolus
• Humulin will use zinc to protamine with insulin complex
• The insulin is created and act based on a basal line
• Some analog will be able to have improved ADME. Lispio is the most used with a rapid acting type.
• While, Glarine is the injection to create subcutanous

Insulin Pros and Cons

• The injections of insulin is lead near of glucemia. The change can rapid depending on their response
• Liver will need up the insulation
• Disrupt well if someone want to lose weight for example.

Regulation

• Good basal needs peak for most constant, which they will have long in process
• Glucose sensitive drug must help a range of action.
• The drugs are not the best and the bodies choices must be good

A Common Approach

• For replacement that will include coverage even if it at night. Then a doctor is referred
• A normal insulin dose during a meal can help that to create the cover of the rapid action that the body.

Type 2

• This will be where it all stems from with the reduced incretin affect. With what goes and reduces.

Goals of Treat

• Mech: Improve function and sensitivity to those with DM
• Clinic: Alleviate the the chronic symptoms.
• Try to add in 2 to start and promote good release.

Exercise for DM

• The ability to workout by using a exercise will to provide help in the glucose.
• It provide an anti biogenesis
• That can lead to a subunits for any other DM situation.

Medical Advice for Pharm

• Be cautious in those in those will suffer a new wave of those to the test the level.
• Provide and increase.