Treatment Of Diabetes Flashcards
What does insulin stimulate through enzymatic activity
Catalyses oxidation of glucose for ATP prod
Polymerises glucose to glycogen
Converts glucose to fat
How does the body respond to insulin deficiency
Decreased uptake of glucose uptake and utilisation
Glycogenolysis
Protein catabolism
Gluconeogenesis
Lipolysis
Ketogenesis
Conditions due to diabetes mellitus
Hperglycemia
Glycosuria - glucose in urine
Osmotic diuresis - increased urine
Lipidemia + ketoacidosis
Ketonuria
Loss of Na and K
Electrolyte and acid base imbalances
Signs and symptoms of diabetes mellitus due to hyperglycaemia
Polyuria - dehydration and soft eyeballs
Poydipsia - thirst
Polyphagia - hunger
Fatigue
Weight loss
Signs and symptoms due to ketoacidosis
Acetone breath
Hypernea
Nausea/ abdominal pain
Cardiac irregularities
CNS depression
How is secretion of insulin regulated
Mostly by glucose levels
GI hormones
Mechanism of how insulin is secreted
Glucose enters beta cells via GLUT 1/3 transporter
Produce ATP (via glycolysis pathway)
Reduces activity of ATP sensitive K channel
Reduces K efflux causing depolarisation (when glucose low beta cell in hyperpolarised state)
Opens Ca channels which cause exocytosis of insulin
Diabetes caused due to glucose transporters becoming:
Unresponsive
Less sensitive
What is biphasic insulin release
Allows glucose to reach cells to be metabolised
2 peaks of insulin secretion
1st peak: stimuli of food causes pancreases to rapidly secrete insulin. Allows feelings of satiety.
2nd peak: when food passed through to stomach to small intestine. Allows glucose absorption.
Which peaks do type 1 and type 2 miss in the biphasic release of insulin
Type 1: both peaks not present
Type 2: 1st peak missing
So diabetes patients can eat more because dont have feelings of satiety (1st peak)
Biological structure of insulin receptor
2 alpha subunits - extracellular binding site
2 beta subunits - transmembrane tyrosine kinase
What happens when substrate binds to insulin receptor
- Phosphorylation of insulin receptor substrate proteins
- Enzyme activation and gene transcription
- Increase in glucose uptake via expression of GLUT 4 transporter
- Increased glycogen synthesis
What are the main groups of drug given by injection
Insulin in various forms/ formulations
Incretin mimetics e.g. exenatide, liraglutide - mimic hormones tat regular activity of insulin (GI hormones)
Main groups of oral drugs
Biguanides - metformin
Sulfonylureas & related drugs
Thiazolidinediones
Gliptins
Glucose transporter inhibitors
Causes of diabetes mellitus type 1
Genetics
Autoimmune response leading to beta cell loss
Management of type 1
Carbohydrate counting
Dietary advice
Managing insulin doses to minimise glucose fluctuations when changing diet (patient specific)
How exercise effects type 1 diabetes patients
Reduced cardiovascular risk
Effects to insulin dosage and carb intake
Regular HbA1c measurement (lower the measurement the better)
Self monitoring of plasma glucose
Finger prick
Continuous monitoring devices
Why does insulin need to be injected
Peptide hormone
Broken down by digestive tract enzymes
Types of human (recombinant DNA) insulin
Short acting: onset 30 mins, peak 2-4 hrs, soluble insulin, insulin lispro
Long acting: onset 1-2 hrs, peak 4-12 hrs, insulin complexes , insulin glargine
Different Dose regimes for insulin
- Short acting 3 times before meals + intermediate/ long acting once or twice
- Pre mixed short and intermediate acting insulin
- Continuous infusion - for patients that poorly manage treatment
Complications of insulin treatment
Fluctuations of blood glucose: hypo/hyper
Allergy
Lipodystrophy - inject to same set can cause change in fat consumption
Contraindications of insulin
Insulin compliance - psychosocial impacts (complex and demanding patients)
Eating disorders
Restrictions - driving/ jobs
Complex cause of diabetes mellitus type 2
Genetics
Socioeconomic factors - poor diet due to poverty
Demographic factors - diff populations have diff likelihood
Causes of type 2 diabetes
No major loss of beta cells
Increased basal insulin levels in blood
Loss of 1st phase of insulin secretion
How is insulin resistance caused in type 2 diabetes
Dysfunction of IR signalling cascade proteins
Associated with inflammation in adipose tissue
Management of Pre diabetic
Vaccine? None successful yet
Primary management of type 2 diabetes
Diet
Exercise
Lifestyle modification
Intermittent fasting
VLCD - very low calorie diet
Type 2 management, if primary defence doesnt work and HbA1c still high:
Drugs (ACE inhibitors, statins)
One third of patients will eventually need insulin
Effects of biguanides (metformin) that lower blood glucose
Decreases gluconeogenesis
Via activation of AMP activated protein kinase (AMPK) - gene expression is decreased
Decreases carbohydrate absorption in intestine
Increases glucose uptake by skeletal muscle
Side effects of using biguanides
No high appetite
Lactic acidosis esp. with alcohol use
Gastrointestinal disturbances
Treatment for obese diabetics
Biguanides with acarbose (reduce carb absorption in gut)
What is acarbose?
Alpha glucosidase inhibitor - decreases CHO absorption
Used for obese
May be gastrointestinal disturbances
Examples of sulfonylureas
Tolbutamide
Glibenclamide
Glipizide
Mechanism of sulfonylureas
Beta cells - bind to SUR (part of K(ATP) channel)
Binding causes channel to close
Depolarisation of beta cell
Ca entry and increases insulin secretion
Secondary effect: Increases tissue sensitivity to insulin
Duration of action of Sulfonylureas
Long acting - glibenclamide (active metabolite 10hr
Short acting - tolbutamide 4hr
Side effects of sulfonylureas
Hypoglycaemia
Diuretic actions
Examples of other SUR modulators
Repaglinide
Nateglinide
What is repaglinide
No sulfonylurea moiety!
Binds to SUR (sulfonylurea receptors) - decreases K(atp) activity
Shorter duration of action: less potent
More selective for K(atp) channels in B cells (as there are K(atp) channels on cardiac cells)
Administered prior to meal
Side effects of SUR drugs
Hypoglycaemia (less with repaglinide)
Stimulate appetite (don’t use for obese patients)
Contraindicated in pregnancy/ breastfeeding
What are SUR and how they can increase insulin secretion
Sulfonylurea receptors in contact with K(atp) channels
Sulfonylurea and glinides (SUR modulators) can bind to SUR
Activation of SUR blocks K(atp) channel
Causing depolarisation
And Ca influx
Increasing insulin secretion
Actions of thiazolidinediones (e.g. pioglitazone)
Binds to TF: affects gene expression
Primary action: adipose tissue. Increase fatty acid uptake and lipogensis
Secondary affect: decreases plasma fatty acids. Increases glucose update. Decreases gluconeogenesis.
Primary action of thiazolidinediones on adipose tissue
Increased fatty acid uptake
Increased lipogenesis
How does insulin affect fatty acid oxidation
Insulin decreases fatty acid oxidation
Decreases triglyceride breakdown
So more fatty acid substrate
Secondary effect of thiazolidinediones on lowering plasma fatty acids
Increased glucose uptake
Decreased gluconeogenesis
Side effects of thiazolidinediones
Weight gain
Liver toxicity
Heart failure due to fluid retention
Used less frequent now due to bad side effects
What are drugs based on incretin actions
Incretins: GI hormones. Created in gut and released after meal regulate insulin.
Regulate insulin secretion
How do incretin acting drugs act like GLP-1 agonists:
Act on pancreas and increase insulin
Slows gastric emptying
Lowers BGL after meal
Induce satiety
What are incretin hormones and examples
GLP-1
GIP
Released from GIT in response to nutritional absorption
What are sodium glucose transporter 2 (SGLT2) inhibitors
Canagliflozin
Rapidly absorbed
Peak plasma conc in less than 2 hours
Examples of sodium-glucose transporter 2 (SGLT2) inhibitors
Empagliflozin
Canagliflozin (usually used in combination)
Mechanism of sodium-glucose transporter 2 (SGLT2) inhibitors
Kidney - proximal convoluted tubule
Increased glucose and Na loss
Promotes osmotic diuresis
So less glucose reabsorbed from tubule
Excess glucose passed out into urine
Cautions and side effects of sodium glucose transporter 2 (SGLT2) inhibitors
- Peripheral vascular disease
Hypotension
Dehydration - Ketoacidosis
Urinary tract infections
What are thiazolidiediones used in combination with
SU (sulfonylureas) or metformin
How do gliptins work
E.g. linagliptin
Block breakdown of incretins
Inhibitors of dipeptidyl peptidase-4 (membrane)
What is exenatide
GLP-1 agonists
Expensive
Used in combination
Slows gastric emptying (for obese)
