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MSc Endocrinology > Diabetes Part 1 > Flashcards

Diabetes Part 1 Flashcards

1
Q

What is Glycolysis?

A
  • Conversion of glucose to pyruvate
  • Production of energy (both directly and by supplying substrate for the tricarboxylicacid cycle (TCA) and oxidative phosphorylation) and to produce intermediates for biosynthetic synthesis
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2
Q

What is Gluconeogenesis?

A
  • Synthesis of glucose from non-carbohydrate precursors (pyruvate, lactate, glycerol & amino acids
  • Mainly occurs in liver and to a lesser extent in the kidneys
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3
Q

What is Glycogenolysis?

A
  • Glycogen mainly stored in liver or skeletal muscle
  • Break down of glycogen to form glucose-6-phosphate
  • This then enters glycolysis to yield energy for muscle contraction
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4
Q

What is Lipolysis?

A
  • Breakdown of lipids
  • Hydrolysis of triglycerides into glycerol and non esterified fatty acids (NEFA)
  • Fatty acid oxidation (β-oxidation) then produces acetyl CoA production and energy in the form of ATP.
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5
Q

What is Ketogenesis?

A
  • When the level of acetyl-CoA from fatty acid oxidation (β-oxidation) increases in excess of that required for entry into the TCA cycle
  • Acetyl-CoA is converted into acetoacetate and D-3-hydroxbutyrate .
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6
Q

What are sources of Glucose?

A
  • Dietary carbohydrate
  • Glycogenolysis (release of glucose from glycogen stores)
  • Gluconeogenesis (glucose synthesis from lactate, glycerol, amino acids)
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7
Q

What is used to control Blood Glucose concentration?

A

Blood glucose concentration primarily vigourously regulated by:

  • Insulin
  • Glucagon

Rarely falling below 2.5mmol/l or rising above 8.0mmol/l

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8
Q

What is the action of Insulin?

A

Stimulates

  • Removal of glucose from blood (via GLUT-4) – skeletal muscle /adipose tissue
  • Glycolysis
  • Glycogen synthesis (in liver)
  • Lipogenesis
  • Protein Synthesis

Inhibits

  • Glycogenolysis
  • Gluconeogenesis
  • Lipolysis
  • Ketogenesis
  • Proteolysis
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9
Q

How is insulin produced?

A
  • Increase in Blood Glucose
  • Beta cells of the pancreatic islets of Langerhans secrete proinsulin
  • Proinsulin is then used to form C-Peptide and Insulin
  • Insulin binds to insulin receptor to activate the GLUT-4
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10
Q

What are the actions of Glucagon?

A

Glucagon increases:

  • Glycogenolysis
  • Gluconeogenesis
  • Ketogenesis
  • Lipolysis

Glycogenolysis

Lipolysis

Glycogenolysis

Lipolysis

Gluconeogenesis

Glycogen synthesis

Proteolysis

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11
Q

What are actions of Adrenaline, Growth Hormone, Cortisol?

A

Adrenaline Increases

  • Glycogenolysis
  • Lipolysis

Growth Hormone

  • Glycogenolysis
  • Lipolysis

Cortisol Increases

  • Gluconeogenesis
  • Glycogen synthesis
  • Proteolysis

Cortisol Decreases

  • Tissue glucose utilisation
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12
Q

What is Diabetes Mellitus?

A

Metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both

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13
Q
A

Worldwide:

  • Approximately over 400 million living with diabetes worldwide
  • Expected to affect >640 million people by 2040

UK:

  • Approx 1 in 16 people in the UK has diabetes (diagnosed or undiagnosed)
  • Since 1996 the number of people diagnosed with diabetes has increased from 1.4 million to 3.5 million (UK)
  • Estimated that >5 million by 2025 (most type 2 with ageing population and increase in obesity)
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14
Q

What are classifications of Diabetes?

A
  • Type 1 Diabetes
  • Type 2 Diabetes
  • Gestational Diabetes (GDM)

Other types related to other causes

  • Genetic defects of beta cell function (eg MODY)
  • Genetic defects of insulin action
  • Diseases of the exocrine pancreas (eg cystic fibrosis, pancreatitis)
  • Endocrinopathies (Acromegley, Cushings)
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15
Q

What is Type 1 Diabetes?

A

Previously known as IDDM (insulin dependent diabetes)

  • Usually diagnosed in younger age (<30 years old)
  • Accounts for 5-10% of all diagnosed cases of DM
  • Insulin deficiency & Ketosis prone
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16
Q

What are types of Type 1 Diabetes?

A

Type 1A : IMMUNE MEDIATED (>90% of T1DM subjects)

  • Pancreatic islets infiltrated with lymphocytes – INSULITIS
  • Autoimmune destruction of pancreatic β cells leading to insulin deficiency. T-Cell trigerring factor unknown
  • Rate of destruction can be variable

Type 1B: IDIOPATHIC (<10% of T1DM subjects)

  • Idiopathic pancreatic β cell destruction
  • No evidence of pancreatic β cell autoimmunity
  • More common in patients of Asian or African origin
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17
Q

What are Targets for Autoantibodies in Type 1 DM?

A
  • Insulin
  • Glutamate decarboxylase
  • Islet antigens
  • Zinc Transporter-8
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18
Q

What are factors that contribute to Type 1 Diabetes?

A
  • Immunological factors
  • Genetic Factors
  • Enviromental Factors
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19
Q

What is Latent Autoimmune Diabetes of Adults?

A

Subtype of type 1 diabetes (Type 1.5 diabetes) with a slower-onset (gradual loss of β cells). Autoantibodies present​

Common characteristics include:

  • Usually > 25 years old at diagnosis
  • Often slim (not always)
  • Can initially be treated by lifestyle changes / oral medication
  • Gradually becomes dependent on insulin (80% within 4 years of diagnosis)
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20
Q

What is Type 2 Diabetes?

A

Previously known as NIDDM (non-insulin dependent DM). ~ 75 - 90% of diagnosed cases of diabetes

Hyperglycemia with:

  • Insulin resistance with relative insulin deficiency, or
  • Insulin secretory defect with or without insulin resistance

Commonly presents in middle age or older age and associated with obesity

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21
Q

What are risk factors of Type 2 diabetes?

A
  • Family History
  • Ethnicity (up to 6 x more common in south asian populations and up to 3 x more common in African and African-Caribbean populations)
  • Obesity
  • Fat distribution
  • Birth weight
  • Physical inactivity
  • Gestational Diabetes
  • Polycystic ovary syndrome (PCOS)
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22
Q

How does Type 2 diabetes develop?

A

Genetic & environmental factors involved

  • Initially compensatory hyperinsulinemia exists
  • Glucose tolerance is near normal despite resistance
  • Impaired glucose tolerance (IGT) then develops
  • Beta cell failure
  • Decreased insulin secretion and increased hepatic glucose production
  • Overt diabetes with fasting hyperglycaemia
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23
Q

What causes insulin resistance?

A
  • Obesity: Most common cause of insulin resistance. 80% of Type 2 DM are overweight. Thought to have receptor and post-receptor effects
  • Ageing: Decreased GLUT-4 transporters possibly
  • Insulin antagonists: Some disorders associated with increased production of insulin antagonists such as cushings syndrome (cortisol), Acromegaly (Growth hormone), Stress states (oxidative stress) eg trauma, surgery, severe infection
  • Medications: Glucocorticoids, cyclosporine, niacin & protease inhibitors
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24
Q

How are central body obesity and insulin resitance related?

A

Central body obesity and insulin resistance are related

  • Increased adipocyte cells leads to increase in free fatty acids & adipokines
  • Results in impaired glucose utilization in muscle
  • Increase hepatic glucose production (gluconeogensis)
  • Impairs pancreatic beta cell function
25
Q

What characteristics linked to obesitymakes up metabolic syndrome?

A

Also known as insulin resistance syndrome or syndrome X

  • Group of characteristics / medical conditions linked to obesity
  • Waist circumference
  • High blood pressure
  • Elevated blood glucose
  • Triglycerides

Increases risk of developing Type 2 Diabetes Mellitus

26
Q

What health disorders are linked to metabolic syndrome?

A
  • Obesity
  • Cardiovascular disease (CVD)
  • Polycystic Ovary Syndrome (PCOS)
  • Non-alcoholic fatty liver disease (NAFLD)
  • Chronic kidney disease (CKD)
27
Q

What is Gestational Diabetes Mellitus?

A
  • Glucose intolerance diagnosed during pregnancy. Resolves after birth (~90% of cases)
  • Occurs in 2-5% of pregnancies
  • Insulin resistance increases during pregnancy which is normally compensated by increased insulin secretion. In GDM patients there is insufficient compensation
28
Q

Which groups of patients should be screend for Gestational Diabetes Mellitus?

A
  • BMI >30
  • Previous macrosomic baby ≥4.5 kg or above
  • Previous GDM
  • First-degree relative with diabetes
  • Family origin with a high prevalence of diabetes (South Asian, black Caribbean and Middle Eastern)
29
Q

What is Maturity of Onset Diabetes of the Young (MODY)?

A
  • Early-onset diabetes usually diagnosed before 25-35 yrs old
  • ~1-2% of people with diabetes have MODY
  • Autosomal dominant inheritance. Caused by a single gene defect altering beta-cell function
  • Obesity unusual
30
Q

What is the most commonly occuring MODY?

A

MODY 3

  • Causes by mutation in HNF1α (Transcription Factor)
  • Decreased insulin secretion, common type, risk of microvascular complications, therapeutic sensitivity to sulphonylurea derivatives
  • 30 - 50% prevelance
  • Sensitive to Sulfonylureas
31
Q

What is Pre-Diabetes?

A

Refers to impaired glucose regulation (IGR). Blood glucose is above the normal but NOT in diabetic range. Indicates the presence of:

  • Impaired fasting glucose (IFG)

and / or

  • Impaired glucose tolerance (IGT)
32
Q

What is the effect of Pre-Diabetes?

A
  • People with pre-diabetes are at increased risk of getting type 2 diabetes.
  • They are also at increased risk of a range of other conditions including cardiovascular disease
33
Q

What are clinical manifestations of Type 1 Diabetes?

A

Polyuria (increased urination)

  • Glucose exceeds the renal threshold causing glycosuria
  • Glycosuria causes osmotic diuresis leading to hypovolemia

Polydipsia (thirst)

  • Increased serum osmolality from hyperglycemia and hypovolemia

Weight loss

  • Loss of water, glycogen & triglycerides
  • Muscle/protein breakdown (amino acids diverted to form glucose and ketone bodies)

Reduced plasma volume

  • Possible symptoms of postural hypotension

Blurred Vision

  • Hyperglycaemia causes alterations to osmotic environment in the lens

Paresthesia (tingling or burning of skin)

  • Peripheral sensory neurotoxicity from sustained hyperglycaemia

Ketoacidosis

34
Q

What are clinical manifestations of Type 2 Diabetes Mellitus?

A

•~ 40% asymptomatic

  • Polyuria
  • Glycosuria
  • Polydipsia
  • Burry vision
  • Fatigue
  • Chronic skin infections
  • Acanthosis Nigricans: Hyperpigmentation of the skin
35
Q

What are Acute Complications of Diabetes?

A
  • Diabetic ketoacidosis
  • Hyperosmolar Hyperglycaemic State (HHS)
  • Hypoglycaemia
36
Q

What are precipitating factors for Diabetic Ketoacidosis?

A
  • Major illnesses (eg Myocardial infarction, pancreatitis)
  • Infection
  • New onset diabetes
  • Inadequate insulin therapy
  • Drugs (eg cocaine, glucocorticoids)
37
Q

How does Diabetic Ketoacidosis develop?

A

Life-threatening: Medical emergency predominately a Type 1 DM complication. Has a rapid onset (within 24 hours)

  • Occurs in uncontrolled diabetes due to Insulin deficiency
  • Counter regulatory hormone excess so increases in glucagon, catecholamines, cortisol and growth hormones
  • Increase in gluconeogenesis & glycogenolysis contributes to hyperglycaemia
  • Increased lipolysis so increased free fatty acid (FFA) delivery to the liver. Free fatty acids are transported into mitochondria: Ketogenesis
  • Ketone bodies are produced: Acetoacetate to acetone / 3-hydroxybutyrate
  • Ketone bodies lower blood pH (metabolic acidosis)
  • Compensatory hyperventilation (Kussmaul respiration possible)
  • Ketones contributes to osmotic diuresis so electrolyte losses
38
Q

What are signs and symptoms of Diabetic Ketoacidosis?

A
  • Nausea & Vomiting
  • Thirst
  • Polyuria
  • Abdominal pain
  • Hyperglycaemia
  • Dehydration
  • Ketotic / Fruity odour
  • Tachycardia
  • Kussmaul breathing
  • Confusion/drowsiness
  • Coma
39
Q

What are laboratory findings for Diabetic Ketoacidosis?

A
  • Hyperglycaemia
  • Hyperosmolality
  • Raised anion gap
  • Ketones in blood / urine
  • Acidosis (blood gas measurement)
  • Reduced Glomerular filtration rate (GFR) – due to hypovolemia
  • Raised urea and creatinine (reduced kidney function)
40
Q

How is Diabetic Ketoacidosis managed?

A
  • Fluid replacement: Restoration of circulatory volume, Clearance of ketones, Correction of electrolyte imbalance
  • Administration of insulin: Hypokalemia often follows treatment (potassium replacement may be needed)
  • Blood ketone and glucose monitoring
  • Venous blood gases
  • Electrolytes
41
Q

What is Hypeerosmolar Hyperglycaemic State?

A
  • Usually occurs in Type 2 DM (middle aged/elderly patients)
  • Precipitating factors similar to DKA
  • Marked hyperglycaemia (higher than DKA) - Frequently >50 mmol/L
  • No acidosis
42
Q

What symptoms of the development of HHS?

A

Develops over several weeks

  • History of polyuria, thirst & weight loss
  • Mental confusion
  • Lethargy or coma can occur

Nausea and vomitting, abdominal pain and Kussmaul breathing normally absent

43
Q

How is Hyperosmolar Hyperglycaemic State managed?

A
  • Rehydration (slow to avoid neurological damage)
  • Insulin (lower doses needed compared to DKA)
44
Q

What are diagnostic criteria for Diabetic Ketoacidosis?

A
  • Plasma Glucose: > 11 mmol/L or known diabetes
  • pH: <7.3
  • Bicarbonate: <15
  • Urine Ketones (Dipstick): Positive
  • Blood Ketones: ≥3
  • Plasma Osmolality: variable
45
Q

What are diagnostic criteria for HHS?

A
  • Plasma Glucose: ≥30 mmol/L
  • pH: >7.3
  • Bicarbonate: >15
  • Urine Ketones (Dipstick): variable
  • Blood Ketones: <3
  • Plasma Osmolality: ≥320
46
Q

What is Hypoglycaemia in Diabetes?

A
  • Most common complication of insulin therapy in Type 1 DM patients
  • Patients can be prone to ‘Hypoglycaemia unawareness’ due to diabetic autonomic neuropathy impairs adrenaline release in response to hypoglycaemia
  • Vulnerable to hypoglycaemia as reduced awareness of signs
47
Q

What are symptoms of Hypoglycaemia in Diabetics?

A
  • Tremor
  • Palpitations
  • Anxiety
  • Sweating
  • Hunger
  • Paresthesias
  • Cognitive impairment
  • Behaviour changes
  • Seizure (severe)
  • Coma (severe)
48
Q

What are Chronic Complications of Diabetes?

A

Microvascular complications

  • Retinopathy
  • Nephropathy
  • Neuropathy

Macrovascular complications

  • Coronary artery disease (CAD) - MI
  • Cerebrovascular disease - Stroke+TIA
  • Peripheral arterial disease (PAD)
49
Q

What is the mechanism for Chronic Complications?

A
  • Some cell types are less effective at regulating intracellular glucose entry e.g. Vascular endothelial cells & neuronal cells
  • These cells are vulnerable to a hyperglycaemic environment
  • There is increased intracellular glucose influx leading to increased mitochondrial superoxide production
50
Q

Which pathways are activated by increased mitochondrial superoxide production?

A

Polyol Pathway = Increased sorbitol concentration

  • Changes redox potential to increase cellular osmolality
  • Generates reactive oxygen species (ROS) leading to oxidative stress

Increased Hexosamine Pathway Activity

  • Gene expression altered = ROS production leading to oxidative stress
  • Increased TCA cycle activity = ROS production leading to oxidative stress

Activation of Protein Kinase C (PKC)

  • Changes gene transcription
  • ROS formation leading to oxidative stress

Advanced Glycosylation End products (AGEs)

  • Non-enzymatic glycosylation of intra/extra-cellular proteins
  • Crosslink proteins
  • Increases atherosclerosis, glomerular dysfunction
  • Changes extracellular matrix composition & structure
  • ROS formation leading to oxidative stress
51
Q

What causes Diabetic Retinopathy?

A

Diabetic complication affecting the eyes

  • Causes damage to the blood vessels of the light-sensitive tissue at the back of the eye (retina)
  • Symptoms may be not be obvious in the early stages but as the condition progresses symptoms may include:
52
Q

What are symptoms presented as diabetic retinopathy develops?

A
  • Spots/dark strings floating in your vision (floaters)
  • Blurred vision
  • Fluctuating vision
  • Dark or empty areas in your vision
  • Vision loss
  • Difficulty with colour perception
53
Q

What are different stages of Diabetic Retinopathy?

A

Early diabetic retinopathy

  • ‘Non-proliferative diabetic retinopathy ‘ stage
  • Damage/weakened blood vessels in retina
  • Retinal vascular micro aneurysms can form
  • Fluid and small amounts of blood can leak into retina
  • Blot hemorrhages
  • Cotton wool spots
  • Macular oedema

Advanced diabetic retinopathy

  • ‘Proliferative diabetic retinopathy ‘ stage
  • Retinal hypoxia/ischaemia
  • •New (abnormal) blood vessel growth
  • Scar tissue can form and cause retinal detachment
54
Q

What is Diabetic Nephropathy?

A

Progressive kidney disease and ain cause of ESRD (End Stage Renal Disease). There are 3 major histologic changes in the glomeruli:

  • Mesangial expansion
  • Glomerular basement membrane (GBM) thickening: Kidneys starts to allowing more albumin than normal in the urine leading to “Microalbuminuria” (30-300mg albumin excretion / 24 hours)
  • Glomerular sclerosis
55
Q

What are Neurological Complications of Diabetes?

A

Diabetic Neuropathy

  • Peripheral nerve dysfunction in particular
  • Occurs in ~50% of patients with long standing Type 1 or 2 DM
  • Can affect all peripheral nerves (sensory, motor or autonomic nerves) with the most common being Distal Symmetric Polyneuropathy
  • Loss of function in a ‘stocking-glove pattern’. Symptoms begin in feet and spreads: Numbness, Tingling, Sharp pain, Burning
56
Q

What are changes that occur in medium to large blood vessels?

A
  • Blood vessel walls thicken
  • Sclerosis
  • Occluded by plaque that adheres to the vessel walls so blood flow is blocked
57
Q

What are the two main factors contributing to Diabetic Foot Disease?

A

Peripheral neuropathy

  • Difficult to perceive injuries due to lack of feeling
  • Increased risk of skin infection

Peripheral artery disease (PAD)

  • Narrowing/occlusion by atherosclerotic plaques of arteries
  • Poor blood flow to feet
  • Difficult to fight infection/heal
58
Q

What infection is common in diabetics?

A
  • Diabetic patients prone to develop foot ulcers
  • In severe cases can lead to amputations

MSc Endocrinology (16 decks)

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