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203: Theme 1 - 304 - Endocrinology > Type 2 DM > Flashcards

Type 2 DM Flashcards

1
Q

What is Diabetes Mellitus?

  • meaning and
  • diagnostic terms
A
  • a condition where the blood glucose is above an internationally accepted levels
  • Usual Clinical diagnosis of blood-
    • Glucose: = or > 11.1mmol/l + symptoms
    • Glucose = or > 11.1 mmol/l x 2
    • HbA1c = or > 48mmol/mol (6.5%)
      • this is Glycohaemoglobin or glycated haemoglobin: a measure of how well-controlled haemoglobin is in the long terms (over a 3 month period). normal levels should be below 5%
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2
Q

Explain the Glucose Tolerance test

A
  • 75 g Glucose Tolerance test
    • Diabetes Mellitus indicated when
      • Fasting plasma glucose = / > 7 mmol/l
      • 2 hour plasma glucose = / > 11.1 mmol/l
    • Impaired Glucose Tolerance indicated when
      • 2-hour glucose between 7 -11 mmol/l
    • Impaired Fasting Glucose indicated when
      • Fasting glucose between 6 – 6.9 mmol/l
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3
Q

What is Type 2 Diabetes Mellitus from a physiological perspective?

A
  • insulin resistance +
  • abnormal beta-cells

which cannot produce enough insulin to keep the blood glucose normal

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4
Q

What damages the Islet cell in T2DM?

A
  • Islet amylin polypeptide polymers secreted from pancreatic islet beta-cells and converted to amyloid deposits
    • seen as green staining in histological samples of T2DM Islet cells
  • there is a deficit in Beta-cells
  • increased beta-cell apoptosis
  • therefore less insulin is produced
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5
Q

What are some aetiological causes of Type 2 diabetes?

A
  • Genetic
    • polygenic
    • Sox5 regulates beta-cell phenotype and is reduced in T2DM
  • Fetal Programming (epigenetic)
    • maternal hyperglycaemia
    • Intrauterine growth retardation
  • Old age
  • Change in gut microbiota
  • Glucotoxity and Lipotoxicity
    • later effects
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6
Q

What fat is associated with T2DM?

A
  • Visceral Fat
  • Epicardial Fat
    • a strong risk for vascular disease
  • Excess fat in the pancreas
    • this is specific to T2DM & is important in preventing normal insulin production
  • Ectopic Fat
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7
Q

What is Ectopic Fat, its effect?

A

And endocrine organ producing

  • Free fatty acids
    • causing insulin resistance
    • these are atherogenic lipids
  • Cytokines
    • causing insulin resistance
    • Inflammation
  • Procoagulant factors (PAI1)
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8
Q

What are the side effects/ morbidities that accompany T2DM?

A
  • Hyperglycaemia
  • Dysregulation of lipid metabolism
  • high levels of proinflammatory cytokines
  • high levels of free radicals
  • increased susceptibility to infection
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9
Q

What is the pathogenesis of retinopathies?

A

induced by the following

  • impaired autoregulation of retinal blood flow
    • maintaining constant blood flow within the relative range is impaired in hyperglycaemia
    • results in increased retinal blood flow –> shear stress in blood vessels
    • causing increased vascular leakage and the production of vasoactive substances
  • accumulation of sorbitol within the retinal cells
    • glucose – (aldose reductase)–> sorbitol
    • consumption of NADPH in the process of NADPH can result in oxidative stress
    • sorbitol accumulation –> alterations in the activity of pkC
    • Protein Kinase C may regulate vascular endothelial growth and regulate vascular permeability
  • accumulation of advanced glycosylation end products (AGEs) in the extracellular fluid
    • AGEs may cross-link with collagen and initiate microvascular complications
    • interaction between AGEs and their receptor RAGE may generate new ROS and cause vascular inflammation
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10
Q

Cataracts in T2DM

A
  • caused by increased generation of polyols from glucose
    • the AR pathway is the initiating factor in diabetic cataract formation
    • leads o osmotic stress in the ens –> apoptosis + increased ROS
  • 1% reduction in HBA1c reduces cataract risk by 19%
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11
Q

the pathological evolution of Diabetic Nephropathy

A
  • Within the first years after the onset of diabetes
    • glomerular hyperperfusion
    • increased glomerular filtration
    • renal hypertrophy
  • Microalbuminuria (30-300mg per day) of albumin in the urine
    • predictor of progression of proteinuria –> decline of GFR
      • patients are at an increased risk of end-stage renal disease and premature CVD
  • Hyperglycemia results in increased ROS and AGEs
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12
Q

Explain the pathogenesis of diabetic neuropathy

  • Metabolic and Vascular risk factors
A

Metabolic and Vascular risk factors contribute to the pathogenesis of diabetic neuropathy

  • Metabolic risk factors
    • ​Advanced Glycosylation End-products (AGEs): advanced glycosylation of essential nerve proteins is implicated in this pathology
    • Sorbitol: accumulation of intracellular sorbitol –> increased cell osmolality, decreased intracellular myoinositol and Na-K-ATPase activity, and slowing in nerve conduction velocity
    • Oxidative stress__: hyperglycemia –> accumulation and stabilization of ROS which damages peripheral nerves
  • Vascular risk factors
    • ​potentially associated with CVD risk factors i.e increased triglyceride, increased BMI, smoking, hypertension
    • Thrombodium and tissue plasminogen activator levels are reduced in peripheral nerve microvessels from diabetic patients
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13
Q

Treating/Preventing T2DM from a Lifestyle perspective

A
  • Diet
    • Eat well plate
    • Mediterranian diet
  • Excercise
    • walking the dog (manageable to patient)
  • Education
    • education programmes e.g Desmond
  • Quit smoking
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14
Q

What medical treatments can be used to treat the following factors within T2DM?

  • Dyslipidaemia
  • Hypertension
A
  • Dyslipidaemia
    • statins
  • Hypertension
    • use of Aspirin
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15
Q

What screens for T2DM complications are there?

  • eyes
  • kidneys
  • feet
A
  • Eyes
    • Retinal Photography
    • Laser treatment when required
  • Kidneys
    • Measure urine albumin ( EMU)
    • Control Blood Pressure
    • ACE inhibitors & ARBs
  • Feet
    • Screen for neuropathy & Vascular disease
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16
Q

Clinical features need to be assessed in a diabetic foot?

A
  • Neuropathy
  • Ischemia
  • Bony deformity
  • Callus
  • Swelling
  • Skin integrity/breakdown
    • between toes and under metatarsal heads
  • Infection
  • Necrosis
17
Q

What is the effect of Insulin in Hepatic cells?

A
  • decrease gluconeogenesis
  • decrease glycogenolysis
  • decrease ketogenesis
  • increases glycogen synthesis
18
Q

What is the effect of Insulin in muscle cells?

A
  • increase GLUT-4 translocation to the membrane
    • increase in glucose uptake
  • increase in glucose oxidation
  • increase in glycogen synthesis
  • increases in amino acid uptake and protein synthesisis
  • decrease in glycogenolysis, and amino acid release
19
Q

What is the effect of Insulin in adipocytes?

A
  • increase glucose uptake
  • increase triglyceride synthesis
  • decrease lipolysis
20
Q

What are the various treatment options for T2DM?

  • what do they specifically target
A
  • Metformin and TZds
    • for Insulin resistance
  • SGLT-2 inhibitors
    • Renal glucose absorption
  • Insulin replacement
    • loss of beta-cell mass
  • Sulphonylureas | GLP-1 analogues | DDP-4 inhibitors
    • beta-cell dysfunction
  • Diet and exercise
    • treats obesity and dyslipidaemia

overall treating hyperglycaemia

21
Q

When is Sulphonylureas indicated as a treatment for T2DM?

  • examples
  • mechanism
A
  • patients who cannot tolerate metformin or ar not a candidate for it
    • if metformin alone is not controlling the glycaemia
  • shorting examples - Glipizide, Gliclazide, are preferred in elderly patients

Action

  • bind to and inhibit the ATP dependant K+ channel in pancreatic beta cells
  • causes depolarization of cell membrane
  • Ca2+ influx –> stimulation of insulin secretion
  • sensitizes B-cells to glucose, decreases lipolysis
  • decreases clearance of insulin the liver
22
Q

What are the side-effects of Sulphonylureas?

A
  • Hypoglycaemia
    • more common with long-acting sulphonylureas
      • glyburide, chlorpropamide
  • most likely to happen after
    • exercise or a missed meal
    • high drug dose,
    • malnourishment
    • alcohol abuse
    • impaired renal or cardiac function, GI disease
    • concurrent treatment with salicylates, sulphonamides, fibrates or warfarin, after leaving hospital
23
Q

What is the action of Biguanide drugs in T2DM?

(metformin)

A
  • they do not stimulate insulin release or cause hypoglycemia
  • biguanides increase glucose uptake in muscle and decrease glucose production by the liver
  • decrease hepatic liver production through AMP-activated protein kinase (AMPK) dependent and independent pathways
24
Q

Go over the mechanism of action of Biguanide drugs

A
  • Suppression of hepatic glucose production through AMPK pathways
    • AMPK increases expression of nuclear transcription factor SHP
    • inhibits the expression of hepatic gluconeogenesis genes PEPCK and G-6-P
  • Increases insulin sensitivity
    • Possibly through improved insulin binding to insulin receptors
  • Enhances peripheral glucose uptake
    • Increased GLUT 4 translocation through AMPK
    • Heart muscle metabolic changes via p38 MAPCK and PKC-dependent mechanisms and independent of AMPK
  • Increases fatty acid oxidation via decreasing insulin-induced suppression of fatty acid oxidation
  • Decreases glucose absorption from GI tract
25
Q

What are the pharmacological properties of metformin?

A
  • orally active
  • doesn’t bind to plasma proteins
  • excreted unchanged in urine
    • half-life 1.3-4.5h
26
Q

What are the indications/ uses of Metformin?

A
  • first line treatment for T2DM unless otherwise contraindicated
    • dose gradually titrated until maximum effective dose reached
  • combined with other anti-diabetic mediation in a single drug
  • also used for polycystic ovary syndrome
27
Q

What are the side-effects and contraindications of Metformin?

A
  • GI side effects
    • nausea, anorexia, abdominal discomfort, diarrhoea, metallic taste in the mouth
  • Lactic acidosis (rare)
    • more frequent in a patient with renal impairment also contraindicated in those with
      • reduced tissue perfusion, infection,
      • cardiac failure, chronic hypoxic lung disease
      • liver disease, or alcohol abuse
      • individuals with a past history of lactic acidosis
  • vit B12 and folate absorption decreased with chronic metformin

an MI or septicemia mandate immediate stoppage

28
Q

What is the mechanism of action of Thiazolidinediones?

A
  • increases insulin sensitivity and the peripheral uptake and utilization of glucose in muscle and fat
  • bind to and activate PPARs which regulate gene expression and regulation of adipocyte lipid metabolism
    • Peroxisome proliferator-activated receptor-gamma
  • may facilitate glucose transport in skeletal muscle
  • may work in regulating the expression of adipose tissue adipokines
  • may reduce hepatic glucose production and improve pancreatic beta-cell dysfunction
29
Q

When are Thiazolidinediones (Glitazones) indicated?

A
  • May be considered when sulphonylureas is contraindicated or when hypoglycaemia is particularly undesirable
  • used when potentially aiming to reduce HbA1c levels
    • pioglitazone may be added to metformin and/ or sulphonylureas in individuals without risk for heart failure or fracture
30
Q

What are the pharmacokinetics of Glitazones (thiazolidinediones)?

A
  • Pioglitazone: taken once or twice a day orally
  • plasma levels peak about 3hr
  • the plasma half-life is 3-7hr; active metabolites (16-24h)
  • metabolised in the liver
  • excreted in faeces (2/3) and urine (1/3)
31
Q

What are the side effects of Glitazones?

  • drug interactions/ contraindications
A
  • cause fluid retention causing oedema and mild anaemia
    • increase the risk of heart failure
  • dose-related weight gain
  • safety in pregnancy and lactation not determined
  • increased incidence of fractures in females treated with rosiglitazone
  • Pioglitazone has many drug interactions as it is metabolised in the liver
    • may lower levels of oral contraceptive drugs containing Ethinyl estradiol and norethindrone
32
Q

What is the effect of Glucagon-Like peptide (GLP-1) analogues

A
  • increase glucose-dependent insulin secretion
  • decrease glucagon secretion and hepatic glucose output
  • regulates gastric emptying and decreases the rate of nutrient absorption
  • decreases food intake
  • decreases plasma glucose acutely to near normal levels
  • has a short duration in plasma
33
Q

Give an example of a GLP-1 and describe it’s the mechanism of action

A

Exanatide

  • administered s.c. injection 30 to 60 mins before last meal of day
  • Facilitates glucose control by;
    • Augmenting pancreas response
    • Suppresses pancreatic release of glucagon helping stop the liver overproducing glucose
    • Slows down gastric emptying
    • Reduces appetite and promote satiety via hypothalamic receptors
    • Reduces liver fat content
  • has a longer duration in plasma than actual GLP-1
34
Q

What are the side effects of GLP-1 analogues?

A
  • Mainly GI problems
    • acid or sour stomach
    • belching
    • diarrhoea
    • heartburn
35
Q

What are Dipeptidyl peptidase-4 (DPP-4) inhibitors?

A
  • Class of oral hypoglycemic agents
  • Mechanism of action is via increased levels of Incretins GLP-1 and GIP
    • Increased Incretins
      • Inhibit glucagon release
      • Increase glucose-induced insulin secretion
      • Decrease gastric emptying
      • Reduce hepatic glucose production
      • Improved peripheral glucose utilisation
  • Drugs in this class include vildagliptin (reversible), sitagliptin (reversible) and saxagliptin (covalently bound)
36
Q

What are Sodium-glucose transport (SGLT) protein inhibitors?

  • examples
A
  • drugs that inhibit the reabsorption of glucose from the proximal convoluted tubule in the nephron
    • SGLT-2 proteins transport glucose against a concentration gradient and the inhibitors blocks this process
  • Dapagliflozin
  • Canagliflozin
37
Q

What are the effects of SGLT2 inhibitors?

A

reversal of hyperglycaemia by inhibitors Na+-Glu cotransporter –> the reversal of glucotoxicity, so these effects are seen

  • increases insulin sensitivity in muscle
    • increased GLUT4 translocation
    • increased insulin signalling
  • Increased Insulin sensitivity in the liver
    • decreased action of glucose-6-phosphatase
  • Decreased Gluconeogenesis
    • decreased Cori cycle
    • decreased PEP carboxykinase
  • Improved beta cell fuction
38
Q

What are the side effects of SGLT2 Inhibitors?

A
  • Rapid weight loss
  • Tiredness
  • Osmotic diuretic –> dehydration
  • Can worsen urinary tract infections and thrush
39
Q

Review the available treatments for T2DM

A

203: Theme 1 - 304 - Endocrinology (15 decks)

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