Case 16 Flashcards
(113 cards)
1
Q
What is Ketogenesis
A
The use of Acetyl-CoA to produce emergency fuel (ketone bodies) promoted by surplus of mobilised fatty acids in starvation. This process in suppressed by insulin
2
Q
What is Glycogenolysis
A
Making glucose available in the fasting state, promoted by glucagon
3
Q
What is Gluconeogenesis
A
Runs in the fasted state and is promoted by glucagon and it is when the body uses “scraps” from a number of different processes (like in amino acid breakdown) and produces glucose from scratch
4
Q
What is Glycogenesis
A
Absorbing surplus of dietary glucose and storing it as glycogen, it is driven by high blood glucose and is suppressed by glucagon
5
Q
Fatty acid biosynthesis
A
Uses surplus carbon substrate to produce fatty acids (FA) for delivery to adipose tissue. It is promoted by insulin and high cellular energy levels (ATP) and is suppressed by glucagon
6
Q
What is amino acid metabolism: disposal of surplus ammonia
A
Surplus ammonia arrives in the liver as glutamate, glutamine or alanine and is de- or transaminated. Nitrogen is eventually disposed as urea (Urea cycle)
7
Q
Explain the simplified pathway of what happens to glucose in the liver in the absorptive state
A
Glucose can be absorbed into the liver via the GLUT-2 transporter, it then gets turned it into Glucose-6-P via glucokinase. This Glucose-6-P can then undergo glycogenesis to become glycogen
OR
Glucose-6-P can go through the pentose phosphate pathway to produce NADPH which helps in the next step
Glucose-6-P undergoes glycolysis to be turned into Pyruvate, then Acetyl-CoA then fatty acids (the step from Acetyl-CoA to fatty acids uses NADPH as a reducing agent) then the fatty acids are turned into Triglycerides by esterified with glycerol, which is then excreted out of the liver as VLDL (very-low-density lipoprotein) which is then sent to tissues to be stored as adipose tissue
8
Q
Generally what does Glycolysis mean and what does it produce at the end
A
Glycolysis is the breakdown of glucose into pyruvate, releasing energy in the form of ATP and NADH, it happens in all tissues and creates pyruvate when you have O2 (aerobic conditions) or lactate (under anaerobic conditions)
9
Q
Explain the simplified pathway of what happens to triglycerides in the fasting state
A
Triglycerides from adipose tissue get turned into fatty acids via lipases which enter the liver. Fatty acids can then be turned into Acetyl-CoA via beta-oxidation (this process produces a lot of energy). Acetyl-CoA can then undergo ketogenesis to create ketone bodies which can be used for fuel
10
Q
Explain the simplified pathways of glucose in the liver in the fasting state
A
It stems from Glucose-6-P
Glycogen can undergo glycogenolysis to make Glucose-6-P.
Acetyl-CoA from fatty acid oxidation can enter the krebs cycle along with lactate and amino acids to form pyruvate, pyruvate can then undergo gluconeogenesis to create Glucose-6-P
Glucose-6-P can then be turned into glucose by Glucose-6-Phosphatase. This glucose produced is then secreted into the blood
11
Q
What is the process of turning pyruvate and other “scraps” (glycerol and amino acids) into glucose called
A
Gluconeogenesis
12
Q
How is glucose turned into triglycerides and when does this usually happen
A
Glucose gets turned into Glucose-6-P via glucokinase, Glucose-6-P then gets turned into pyruvate —> Acetyl-CoA —> Fatty acids —> triglycerides
Happens in the absorptive state
13
Q
Explain glycolysis generally
A
Glycolysis is the breaking down of glucose (and most other carbs via glucose) in all tissues. It involves the breakdown of glucose into Glucose-6-P into a bunch of other stuff into pyruvate, releasing energy in the form of ATP and NADH.
glycolysis itself does not need oxygen but when there is a lack of oxygen the pyruvate gets turned into lactate which is toxic
14
Q
Why is glucose converted into Glucose-6-P
A
This is a process called phosphorylation and it is so the cell traps the glucose inside, as it is hard for a cell that has a phosphate group to leave a cell. This process is done by the enzyme glucokinase
15
Q
The liver converts lactate back to pyruvate; TRUE or FALSE
A
True
16
Q
Explain the structure of Glycogen
A
Is a highly branched, all-glucose poly-saccharide with an α-1,4-linked backbone and α-1,6-linked branches
It has a lot of branches because glucose can only be mobalised from the tips so branching increases the amount of ‘tips”
17
Q
What effect does glucagon have on glycogen metabolism?
A
Glucagon promotes glycogenolysis (breakdown of glycogen) and inhibits glycogenesis (synthesis of glycogen).
18
Q
How does glucagon exert its function
A
Glucagon binds to its receptor on liver cells, triggering cAMP production. cAMP activates protein kinase A (PKA), which First:
- It inactivates glycogen synthase to stop glycogen synthesis.
THEN SECOND
- Protein kinase A activates phosphorylase kinase which activates activates glycogen phosphorylase (or you can just say Protein kinase A activates glycogen phosphorylase) leading to glycogen breakdown
This promotes glycogenolysis and inhibits glycogenesis.
Glucagon is also the key activator of Gluconeogenesis
19
Q
What feeds gluconeogenesis and what is the primary activator
A
- Lactate from skeletal muscles can be re-oxidised to pyruvate and turned into glucose (remember pyruvate can be turned into glucose but once it is turned into Acetyl-CoA it cant)
- Glycerol from the metabolism of triglycerides can be turned into glucose
- Amino acids from tissue proteins are transanimated into alpha-keto acids which can also be turned into glucose
Primary activator is glucagon, it does this by preventing the conversion of pyruvate into Acetyl-CoA because if that happens it can no longer be turned back (and no longer be able to turned into glucose)
20
Q
Explain the steps of lipogenesis
A
Lipogenesis begins with the transport of acetyl-CoA from the mitochondria to the cytoplasm via the citrate shuttle (Citrate) , where it is converted to malonyl-CoA by acetyl-CoA carboxylase (the rate-limiting step). Fatty acid synthase then elongates the growing fatty acid chain by adding two-carbon units from malonyl-CoA, using NADPH as a reducing agent
(NADPH is produced from Glucose-6-P in the pentose phosphate pathway)
Once the fatty acids are synthesized, they are esterified with glycerol to form triglycerides, which are stored in adipose tissue or secreted as VLDL by the liver. The process is highly regulated by insulin, which activates key enzymes and promotes energy storage.
21
Q
What is transamination in amino acid metabolism? and what enzyme does this
A
Transamination is the transfer of an amino group from an amino acid to an α-keto acid, forming a new amino acid and an α-keto acid. It is catalyzed by aminotransferase enzymes like ALT (Alanine Transaminase) and AST (Aspartate transaminase)
22
Q
What is deamination in amino acid metabolism?
A
Deamination removes an amino group from an amino acid, releasing ammonia (NH₃) and producing an α-keto acid. It can be oxidative (via glutamate dehydrogenase) or non-oxidative.
Ammonia is transported as glutamine or alanine to the liver, where it enters the urea cycle for safe excretion as urea.
23
Q
What happens to surplus amino acids
A
They are recycled, redistributed, or degraded into:
Pyruvate (for gluconeogenesis or energy).
TCA cycle intermediates (for energy or biosynthesis).
Acetyl-CoA (for fatty acid synthesis or energy).
24
Q
What are the main types of lipoproteins involved in fat transport?
A
Chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
25
What is the role of chylomicrons and VLDL in fat transport?
- Chylomicrons transport dietary triglycerides and cholesterol from the intestines to the liver, adipose tissue, and muscles.
- VLDL is produced by the liver and delivers endogenous triglycerides and cholesterol to peripheral tissues.
26
What is the significance of LDL in lipid metabolism?
LDL carries cholesterol to peripheral tissues but is often referred to as "bad cholesterol" because excess LDL can deposit cholesterol in arterial walls, leading to atherosclerosis.
27
What is the role of HDL in fat transport?
HDL collects excess cholesterol from tissues and transports it back to the liver for excretion or recycling, often referred to as "good cholesterol."
This process is also known as reverse cholesterol transport
28
What do you get when pancreatic lipase breaks down triglycerides
2 fatty acids and one monoglyceride
29
What are the main transporters for glucose in glucose homeostasis (and where are the in the apical membrane vs basolateral membrane)
- Passive glucose transporters (GLUTs) (just glucose)
- Sodium-Glucose linked transporters (SGLTs) (uses sodium's gradient to transport glucose into the cell)
Apical membrane:
- GLUTs and SGLTs
Basolateral membrane:
- GLUTs only
30
What are the two SGLT transporters and what can their mutation cause
- You have SGLT1 and SGLT2
- SGLTs are insulin-insensitive transporters meaning they don't need insulin to transport glucose
- SGLT1 transports 2 Na for 1 Glucose
- SGLT2 transports 1 Na for 1 Glucose
- SLC5A1 codes for SGLT1 and a mutation causes glucose-galactose malabsorption
- SLC5A2 codes for SGLT2 and a mutation causes familial glucosuria (presence of glucose in urine)
31
Where are SGLT1 mostly found
Mostly in the Gastrointestinal tract (particularly duodenum and jejunum) and also some in the late proximal convoluted tubules (S3) of the kidney
32
Where are SGLT2 mostly found
- SGLT2 is mostly found in the proximal early convoluted tubule (S1, S2) of the kidney which is why it causes glucosuria in its mutation (it abosrbs 90% of the glucose in the kidney)
33
What are the main GLUTs transporters you need to know and give some info on them
- GLUT 1, GLUT 2 and GLUT 4
- GLUT1 (brain) and GLUT2 (liver, pancreas and kidney) are insulin insensitive by are critical to glucose absorption (GI tract, renal, hepatic) and glucose signalling.
- In the islets GLUT2 is responsible for insulin secretion
- GLUT4 is insulin-sensitive meaning it needs insulin to transport glucose, it is located in adipose tissue, striated muscle and the heart
34
What are the affinities of the GLUT transporters for glucose
GLUT4 and GLUT1 have similar km (affiinity) for glucose, approx 5mM
GLUT2 has high affinity/km for glucose at approx 17mM
35
Describe glucose's journey from the small intestine to the blood
Enters the enterocytes in the small intestine via SGLT1 transporter which transports 2Na with one glucose into the cell, it then leaves the cell from the basolateral membrane into the blood via the GLUT2 (GLUT1 more in brain [blood-brain barrier] and RBCs, GLUT4 is insulin sensitive so thats why its GLUT2). Once in the blood it can free-float till it reaches its target organ or it can enter RBCs via GLUT1
36
Where in the nephron does glucose reabsorption take place
Glucose is absorbed by the proximal convoluted tubule (PCT), 90% of it is absorbed via SGLT2 in the early PCT and almost all of the remaining is absorbed in the late PCT via SGLT1
SGLT2 first then SGLT1 (first u want a little sodium in so SGLT2 then more sodium so SGLT1)
37
Describe glucose-induced insulin release
Glucose enter beta-cells in the islets of langerhans via GLUT1 and GLUT2, this leads to the metabolism of glucose in the cell leading to the release of ATP, ATP then causes the closure of potassium gated channels, preventing K+ from exiting the cell, this causes depolarisation which leads to calcium channels opening and an influx of Ca2+ to enter the cell, finally this causes the exocytosis of insulin
38
How does GLP1 cause insulin release and where does GLP1 come from
GLP1 (Glucagon-like peptide) is released by enteroendocrine L-cells in the gut in response to nutrients. They then travel through the blood and bind to GLP-1 receptors on the B-cells. Once binded this stimulates G-proteins which causes cAMP production which leads to protein kinase A activation which leads to the exocytosis of insulin
39
Name three tissues highly sensitive to insulin.
Liver, skeletal muscle, and adipose tissue.
40
What are the primary effects of insulin on metabolic pathways?
Insulin stimulates pathways like glycolysis and glycogen synthesis and inhibits pathways like gluconeogenesis and lipolysis.
41
How does insulin impact glucose uptake in insulin-sensitive tissues?
It causes the translocation of GLUT4 transporters to the cell membrane, increasing glucose uptake.
42
How does insulin receptor activation lead to glucose uptake?
Insulin binds to its receptor, activating tyrosine kinase, which triggers signaling cascades like IRS and PI3 kinase, leading to GLUT4 translocation.
43
What role does insulin play beyond glucose homeostasis?
Insulin is involved in growth, lipid metabolism, mitogenesis, reproduction, cognition, and inhibition of apoptosis and autophagy.
44
Diabetes Mellitus definition
Metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action or both
45
Type 2 diabetes definition
Metabolic disorder caused by insulin resistance and insulin deficiency resulting in hyperglycaemia
46
What is pre-diabetes
People at high risk of developing type 2 diabetes
47
Name other forms of diabetes besides type 1 and type 2.
Gestational diabetes, steroid-induced diabetes, type 3C diabetes (e.g., pancreatitis-related), and cystic fibrosis-related diabetes.
48
What the blood test is commonly used to diagnose type 2 diabetes today and what scores indicate what?
HbA1c, or glycated hemoglobin, is a blood test that measures the average level of blood sugar (glucose) over the past 2-3 months with a threshold of 48 indicating type 2 diabetes. and a threshold of 42 indicating high risk for type 2 diabetes
glycated haemoglobin is somthing that forms when haemoglobin binds with glucose in the blood, and since RBCs live for 2-3 months it can indicate your avergae blood sugar in that time period
49
Describe the oral glucose tolerance test (OGTT) procedure and what are two pre-diabetic conditions identified by it
A patient consumes 75 grams of glucose, and blood glucose levels are measured at 1 and 2 hours post-ingestion.
Impaired glucose tolerance and impaired fasting glucose.
50
What are the 3 diagnostic blood marker to test for type 2 diabetes
- HbA1c, or glycated hemoglobin
- Oral glucose tolerance test (OGTT)
- FPG, Fasting plasma glucose
51
Insulin suppresses Glucagon: TRUE or FALSE
True
52
What percentage of diabetes does type 2 account for
90%
53
Is diabetes more common in men or women and what age group does it affect the most, and what ethnicities
More common in men and the 65+ age group is most affected, there is also an increasing amount of people getting diagnosed under 40.
3-5 times increased prevalence in ethnic minority groups vs white communities, with earlier onset in south asians (india, pakistan) and African-caribbean (ethnicity matters because south asians for example have more abdominal fat, more insulin resistance, increased inflammatory response, more dyslipidemia)
54
What kills the people the most with type 2 diabetes and what can it cause
- Cardiovascular disease cause of death in ~70%
- Commonest cause of chronic kidney disease
- Commonest cause of lower limb amputation
- Commonest cause of blindness in working population
- Metabolic dysfunction-associated steatotic liver disease (MASLD) – most common liver disease in world
- 10% of NHS Budget
55
What is insulin resistance and what causes it
Insulin resistance occurs when cells in the liver, muscle, and adipose tissue do not respond effectively to insulin, impairing glucose uptake and leading to hyperglycemia.
The main causes are genetics, obesity, physical inactivity, increased visceral fat releasing inflammatory cytokines, and free fatty acids interfering with insulin signaling pathways.
56
What does Insulin resistance lead to
- Hyperglycaemia
- Increased lipolysis
- Increased proteolysis
- Increased hepatic gluconeogenesis
57
Insulin leads to increased expression of GLUT4 transporters on the surface of the cell which allows more insulin in, when insulin receptors are defective it means less of these transporters can be expressed: TRUE or FALSE
True
58
What damages beta cells and what does that lead to
Beta cells damaged by:
- Increasing amyloid deposits
- Chronic low level Inflammation caused by excess fat
- Glucotoxicity
- Lipotoxicity
Beta cells initially compensate for insulin resistance by producing more insulin, but over time, chronic stress and these previous factors leads to beta-cell exhaustion, reduced insulin secretion, and eventual failure. this failure leads to insufficient insulin secretion which worsens hyperglycemia, contributing to the progression of type 2 diabetes.
59
How does the liver contribute to hyperglycemia in type 2 diabetes?
The liver fails to suppress glucose production due to insulin resistance, leading to increased gluconeogenesis and glycogenolysis, which worsen hyperglycemia. Also glucagon levels are usually inhibited by insulin so glucagon levels can elevate leading to more Gluconeogenesis and Glycogenolysis.
60
How are incretin hormones affected in type 2 diabetes?
Incretin hormones (GLP-1 and GIP) (GLP is released from enteroendocrine L-cells and GIP is released by enteroendocrine K-cells) that enhance insulin secretion after meals are impaired, leading to reduced post-meal insulin production.
61
What are the effects of chronic hyperglycemia and lipotoxicity in type 2 diabetes?
Chronic hyperglycemia damages tissues (glucose toxicity), worsening beta-cell function. Excess free fatty acids accumulate in the liver and muscles (lipotoxicity), impairing insulin sensitivity further. Chronic low-grade inflammation from fat tissue and high glucose levels exacerbates also insulin resistance and vascular damage.
62
What vascular complications arise from type 2 diabetes?
High glucose levels damage blood vessels, leading to complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease.
63
What are the key features of type 2 diabetes pathophysiology?
1. Insulin resistance in peripheral tissues (muscle, fat, liver).
2. Beta-cell dysfunction and reduced insulin secretion.
3. Hepatic overproduction of glucose.
4. Impaired incretin effect.
5. Chronic hyperglycemia and glucose/lipid toxicity.
64
How does the pathophysiology of type 2 diabetes create a cycle of progression?
Insulin resistance worsens beta-cell failure, leading to progressively higher blood glucose levels, which further exacerbates insulin resistance and beta-cell dysfunction.
65
Risk factors of type 2 diabetes
Non-modifiable:
- Age
- Ethnicity
- Family history
- Low birth weight
- History of GDM
Modifiable
- Obesity- Approximately 80% of the risk for developing T2DM
- Hypertension
- Dyslipidaemia (low HDL, high triglycerides)
- PCOS (Polycystic ovary syndrome)
- Poor dietary habit (low fibre, high glycemic index diet)
66
What are the signs and symptoms of Type 2 diabetes
- Asymptomatic (for most people)
- Polyuria and nocturia: (Nocturia, the need to wake up at night to urinate, Polyuria, in general, refers to excessive urine production throughout a 24-hour period)
- Polydipsia (excessive thirst)
- Lethargy (lack of energy)
- Weight change (weight loss once severe insulin deficiency occurs)
- Thrush/genital itching
- Prolonged healing time
- Visual disturbance
67
Why does type 2 diabetes cause polyuria, nocturia, and polydipsia?
Type 2 diabetes causes these symptoms due to high blood glucose levels:
Polyuria & Nocturia: When blood glucose exceeds kidney's reabsorption capacity, excess glucose spills into urine, drawing water with it, leading to increased urine output (polyuria) and frequent nighttime urination (nocturia).
Polydipsia: The body loses water through increased urination, causing dehydration, which triggers intense thirst (polydipsia) as the body seeks to replenish fluids.
68
How do u diagnose diabetes type 2
Diabetes symptoms (e.g. polyuria, polydipsia) plus:
- HbA1c of >48mmol/mol or
- A random venous plasma glucose concentration ≥ 11.1 mmol/l or
- A fasting plasma glucose concentration ≥ 7.0 mmol/l or
- two hour plasma glucose concentration ≥ 11.1 mmol/l two hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT).
With no symptoms:
Two separate positive results from separate days (any two of above but in common practice HbA1c used)
69
When do you not use the HbA1c
- Rapid onset of diabetes: HbA1c levels may not reflect recent changes in blood glucose until a few weeks later.
- Pregnancy: HbA1c is typically lower during pregnancy, which can lead to inaccurate results.
- Conditions with altered red blood cell survival: Conditions like haemoglobinopathies, hemolytic anaemia, severe blood loss, splenomegaly, and antiretroviral drugs can impact HbA1c levels.
- Increased red cell survival: After a splenectomy, where red blood cell survival is prolonged, HbA1c levels may be falsely elevated.
- Renal dialysis: Dialysis, especially with erythropoietin treatment, can lower HbA1c levels.
- Iron and B12 deficiency: Deficiencies and their treatments can alter red blood cell turnover, affecting HbA1c levels.
70
What are the aims of treatment of type 2 diabetes
- Remission
- Improved glycaemic control
71
What is the non-pharmalogical management of type 2 diabetes
- Lifestyle modification – NHS diabetes prevention programme (DPP)
- ASSESS Cardiovascular risk – e.g. QRISK2/3
- Diet + Exercise
- Weight loss – Aim 10% reduction
(Can be enough to put Type 2 Diabetes into remission – DiRECT study 2019)
- Smoking cessation
72
What type of surgery can u undergo for type 2 diabetes
Bariatric surgery (weight loss surgery)
73
What is the Pharmalogical treatments of type 2 diabetes
- Metformin
- SGLT2 inhibitors
- Sulphonylurea
- DPP4 inhibitors
- Thiazolidinediones
- GLP-1 analogues
- Insulin
74
What does metformin do and what are their side effects
- Reduces insulin resistance and hepatic glucose output
- Reduces weight
- Appetite suppressing effects
- Exact mechanism not known – AMPK? GDF15?
- Dosage: 500mg OD , increase stepwise to 1g BD
- Side effects: diarrhoea, nausea, anorexia, lactic acidosis
75
What do SGLT2 inhibitors do and what are their side effects
- Reduce glucose reabsorption from proximal tubule of nephron which means less glucose gets put back in the blood circulation, also have diuretic effect (good for heart failure patients)
- Combination therapy in most patients
- Can be used as monotherapy in specific cases
- Additional effects: Weight loss, blood pressure lowering, CVD protection, Renal Protection (good for chronic kidney disease)
- Dosage: Dapagliflozin 10mg OD, Canagliflozin 100mg – 300mg, Empagliflozin 10-25mg
- Side effects: increased risk of urinary tract infection, Euglycemic diabetic ketoacidosis (EDKA) is a form of diabetic ketoacidosis (DKA) where blood glucose levels are within the normal range (euglycemic), but the body still produces and accumulates ketones, leading to metabolic acidosis
76
How does Sulphonylurea work and side effect
Insulin is released because glucose enters GLUT-2 channels which activates cAMP --> protein kinase A which causes the ATP-sensitive K+channels to close, this leads to depolarisation and Ca2+ channels to open which leads to insulin exocytosis.
The ATP-sensitive K+ channels have a SUR-1 receptor where sulphonylurea binds, this causes the K+ channel to stay closed and sustained depolarisation of the beta cell leads to more insulin being released
Dosage: gliclazide 40mg OD, increased to 320mg in divided doses if needed
Side effects: hypoglycaemia, weight gain
77
How do DPP4 inhibitors work
DPP4 enzymes break down GLP-1 which has an insulin effect. DPP4 inhibitors prevent the action of this enzyme which prevents breakdown of incretins, preserving incretin effect.
Usually combination therapy with metformin/ metformin + sulphonylurea
Monotherapy if metformin or sulphonylurea intolerant
Dosage: alogliptin 25mg OD, saxagliptin 5mg OD
Side effects: GI disturbance, rash, headache, sore throat
78
How do Thiazolidinediones work
Thiazolidinediones enter adipocytes and bind to the PPARgamma receptor in the nucleus and promotes insulin-sensitive gene transcription which promotes the uptake of glucose into the adipocyte and storage and also influences fatty acid transport into the cell to increase lipogenesis
Dosage: pioglitazone 15mg OD, increased to 45mg OD if required
Side effects: ↑fracture risk, fluid retention, heart failure, small ↑ risk of bladder cancer
79
How do GLP-1 analogues work and what are the popular brands
Semaglutide (branded as Ozempic) and Tirzepatide (branded as Mounjaro)
80
When should insulin therapy be considered and what are some reasons for not initiating therapy
Insulin therapy should be considered if:
- Inadequate control despite dual therapy (metformin plus another oral antidiabetic drug)
- Oral antidiabetic drugs are contraindicated or not tolerated.
Reasons for not initiating therapy:
- Obesity
- Physical and mental health - Hypoglycaemia
- Anxiety about needles
- Personal preference
- Concerns relating to license to drive group 2 vehicles
81
How is insulin given
Neutral Protamine Hagedorn (NPH) insulin (injected once or twice daily according to need)
NPH plus a short acting insulin should be considered if HbA1c is 75 mmol/mol higher
OR
Longer acting insulin analogues e.g. insulin detemir or insulin glargine
82
What are examples of SGLT2 inhibitors
(-flozin)
- Dapagliflozin
- Canagliflozin
- Empagliflozin
83
What are the treatment targets for type 2 diabetes
- HbA1c <48mmol/mol if not on medication which cause hypoglycaemia ( otherwise <53mmol/mol)
- BP <140/80 (<130/80 if complications present)
- Total cholesterol <4.0 mmol/l, LDL<2.0 mmol/l, HDL >1 (men) >1.2 (women)
84
What are the long-term complications of diabetes that affect every part of the body
Microvascular complications:
- Diabetic retinopathy
- Diabetic Nephropathy
- Diabetic Neuropathy
Macrovascular Complications:
- Stroke
- Heart disease
- Peripheral vascular disease
85
Mechanism of diabetic retinopathy
Mechanism:
Chronic hyperglycemia damages retinal capillaries through oxidative stress and AGE (Advanced Glycation End-product) formation.
Increased vascular permeability leads to macular edema.
Neovascularization (formation of new, fragile blood vessels) occurs in response to ischemia, predisposing to bleeding and vision loss.
Result: Progressive vision impairment and potential blindness.
86
Mechanism of diabetic nephropathy
Mechanism:
High glucose levels trigger glomerular hyperfiltration and damage the glomerular basement membrane.
Protein glycation and oxidative stress lead to thickening of the membrane and loss of podocytes (key filtration cells).
Microalbuminuria progresses to macroalbuminuria and eventually kidney failure.
Result: Chronic kidney disease and end-stage renal disease.
87
Mechanism of diabetic neuropathy
Mechanism:
- Chronic hyperglycemia disrupts nerve function through polyol pathway activation, which depletes nerve cell energy (ATP) and increases sorbitol accumulation.
- Oxidative stress and microvascular damage to vasa nervorum (blood supply to nerves) result in nerve ischemia and damage.
- Result: Loss of sensation (peripheral neuropathy), pain, and autonomic dysfunction.
- Polyol Pathway Activation:
Chronic Hyperglycemia: Excess glucose enters the polyol pathway.
Aldose Reductase Activity: Converts glucose to sorbitol, which accumulates in cells.
Energy Depletion: Sorbitol buildup disrupts ATP production and cellular osmotic balance.
- Oxidative Stress:
Sorbitol accumulation reduces levels of NADPH, an essential cofactor for regenerating glutathione (a major antioxidant).
Reactive Oxygen Species (ROS): Increased oxidative stress damages nerve cells and supporting structures.
- Microvascular Compromise:
Damage to the vasa nervorum (tiny blood vessels supplying nerves).
Ischemia: Reduced oxygen and nutrient delivery to nerves results in nerve fiber damage and eventual atroph
88
What is the diabetic retinopathy classification
89
Prevention and treatment of diabetic retinopathy
- Glycaemic control
- Blood pressure control
- Annual screening
Treatment:
- Photocoagulation - a medical procedure using intense light, typically from a laser, to create heat and burn tissue, often used in the eye to treat conditions like diabetic retinopathy, macular degeneration, and retinal tears. The laser is used to seal off abnormal blood vessels, destroy tissue, and create scar tissue to repair damage
- Anti-VEGF therapy - Anti-VEGF therapy is a treatment approach that uses medications to block vascular endothelial growth factor (VEGF), a protein that promotes the growth and leakage of blood vessels. These treatments are primarily used to address conditions causing abnormal blood vessel growth or swelling in the retina, like age-related macular degeneration (wet AMD) and diabetic retinopathy
- Surgery
90
What are the 4 forms of diabetic neuropathy in which it can present
- Distal symmetrical sensorimotor polyneuropathy & small fibre neuropathy (affects extremities) (peripheral neuropathy)
- Radiculopathies: (involves nerve damage causing pain, often unilateral, in areas like the thighs, hips, or buttocks, and can affect the abdomen or chest)
- Mononeuropathy: Sudden damage to a single nerve or a group of nerves, often localized (can affect cranial nerves)
- Autonomic neuropathy: Damage to the autonomic nervous system, which controls involuntary body functions.
91
Describe peripheral neuropathy
Pain and loss of sensation
Pain is described as:
- Burning
- Paresthesia
- Persistent hyperaesthesia
- Nocturnal exacerbation
92
What can autonomic neuropathy cause
- Postural hypotension
- Diabetic gastroparesis (Diabetic gastroparesis is a condition where the stomach takes longer than usual to empty its contents,)
- Small bowel bacterial overgrowth (dirrahea)
- Cardiac autonomic neuropathy (a serious complication of diabetes where nerve damage disrupts the autonomic nervous system's ability to regulate heart rate and blood pressure)
- Urogenital (bladder emptying problems)
93
Neuropathy treatment
94
Causes of Diabetic Foot
Peripheral Neuropathy:
- Sensory: Loss of pain/temperature sensation → unnoticed injuries.
- Motor: Muscle atrophy → foot deformities (e.g., claw toes).
- Autonomic: Dry, cracked skin → infection risk.
Peripheral Arterial Disease (PAD):
- Reduced blood flow → ischemia, poor wound healing.
- Immunosuppression:
- Hyperglycemia impairs neutrophil and macrophage function → increased infection risk.
Trauma & Repetitive Stress:
- Ill-fitting shoes/friction → skin breakdown.
Microvascular Dysfunction:
- Damaged capillaries → reduced oxygen/nutrient delivery.
95
What is diabetic nephropathy?
A serious kidney complication caused by chronic high blood sugar levels, characterized by damage to the kidney's filtering system (glomeruli).
96
What are the main causes of diabetic nephropathy?
Chronic hyperglycemia, hypertension, genetic predisposition, and lifestyle factors like smoking and obesity.
97
What is the key diagnostic test for detecting kidney damage in diabetic nephropathy?
- The Albumin-Creatinine Ratio (ACR).
- Moderately increase albuminuria (Microalbuminuria)
98
What is nephropathy defined as (test result)
- An ACR >= 30mg/mmol
- or dip-stick positive proteinuria
- or urinary albumin concentration of >= 200mg/L
99
What are the main symptoms of advanced diabetic nephropathy?
Proteinuria (foamy urine), oedema, fatigue, poor appetite, and uncontrolled high blood pressure.
100
What are the stages of nephropathy
G1, G2, G3 (G3a, G3b), G4 and G5, that is compared to ACR (albumin-creatinine ratio)
101
What is the most common and feared adverse effect of insulin therapy?
Hypoglycemia
102
How does hypoglycemia affect diabetes management?
It creates fear, anxiety, and reduces adherence to intensive insulin regimens, often preventing patients from reaching target A1C levels.
103
Describe the "vicious cycle" of hypoglycemia.
One episode of hypoglycemia increases the risk of subsequent episodes, especially in type 1 diabetes.
104
What are the key counter-regulatory hormones that respond to falling blood glucose levels?
Glucagon.
Epinephrine.
Growth hormone and cortisol (important in prolonged fasting).
105
What happens when blood glucose falls below 2.8 mmol/L?
Cognitive impairment occurs.
106
What is impaired awareness of hypoglycemia (IAH)?
A condition where patients lose the warning symptoms of hypoglycemia, increasing the risk of severe episodes.
107
List some acute and long-term effects of severe hypoglycemia.
Acute: Seizures, coma, arrhythmias, and death.
Long-term: Cognitive decline, increased A1C, weight gain, and mental health issues like depression.
108
Why is good education important for managing type 1 diabetes?
Because diabetes management is largely self-directed, requiring skills like carbohydrate counting and insulin dose adjustment.
109
What are the two main types of insulin therapy regimens?
Multiple Daily Injections (MDI).
Insulin Pump Therapy.
110
What are basal and bolus insulins?
Basal Insulin: Long-acting insulin to mimic background insulin.
Bolus Insulin: Rapid-acting insulin given at meals to handle food intake.
111
What is a closed-loop insulin delivery system?
A system that combines CGMs and insulin pumps with algorithms to automate glucose control, known as an artificial pancreas.
112
Summarize the role of the hypothalamus in the regulation of thirst.
The hypothalamus regulates thirst primarily through the osmoreceptors in the preoptic area, which detect changes in blood osmolarity (salt concentration). When osmolarity increases (e.g., during dehydration), these receptors signal the hypothalamus to initiate thirst. This is crucial for maintaining fluid balance.
ADH (Antidiuretic Hormone): The hypothalamus also stimulates the posterior pituitary gland to release ADH. ADH acts on the kidneys, promoting water retention and decreasing urine output.
Angiotensin II: Another signal involved in thirst regulation is angiotensin II, which is triggered by a decrease in blood volume (e.g., due to dehydration or blood loss). It signals the hypothalamus to increase thirst and stimulate ADH release.
Thirst Sensation: As a result, the body seeks to replenish lost fluids by driving the sensation of thirst, ensuring proper hydration.
113
Summarize the role of the hypothalamus in the regulation of hunger.
The hypothalamus regulates hunger by responding to hormones that signal the body's energy status:
Ghrelin: Released by the stomach when it's empty, signals the hypothalamus to trigger hunger.
Leptin: Produced by fat cells, signals satiety and reduces hunger when energy stores are full.
The lateral hypothalamus stimulates hunger when energy is low, while the ventromedial hypothalamus promotes satiety after eating.
