Diabetes Flashcards
How many people in the UK have diabetes?
Approximately 4.9 million people have diabetes in the UK
How many people in the UK are at increased risk for Type 2 diabetes?
13.6 million people in the UK are at increased risk for Type 2 Diabetes
What percentage of people have Type 1 Diabetes?
10% of people have Type 1 Diabetes
What percentage of people have Type 2 Diabtes?
90% of people have Type 2 Diabetes
To diagnose Pre Diabetes what does the Impaired Glucose Tolerance tests need to show?
Pre Diabetes Diagnosis ( Impaired Glucose Tolerance) Fasting plasma glucose: <7.0mmol/l AND 2-h plasma glucose >/= 7.8mmol/l to 11.1 mmol/l
Which two tests diagnose pre diabetes?
Impaired glucose tolerance and Impaired fasting glucose
When do pregnant women have their routine glucosuria test?
Pregnant women have their routine glucosuria test between week 12 and 14
What is HbA1c?
HbA1c= Glycosylated haemoglobin: haemoglobin bound to glucose
What does HbA1c measure?
HbA1c measures the average blood glucose over 8-12 weeks
What does high HbA1c indicate?
High HbA1c indicates high blood glucose
HbA1c units
Current vs New
6.0% vs
6.5% vs
7.0% vs
7.5% vs
HbA1c units
Current vs New
6.0% vs 42 mmol
6.5% vs 48 mmol
7.0% vs 53mmol
7.5% vs 59 mmol
When is HbA1c not used?
HbA1c is not used to diagnose:
People under the age of 18
Suspected Type 1 diabetes
Pregnancy diagnosis
Which tests are used to differentiate for Type 1 diabetes?
A Glutamic Acid Decarboxylase Autoantibodies test
C-peptide (pro insulin)
Which tests are used to differentiate for gestational diabetes?
FBG
OGTT
HbA1c: but cut off is lowered
Which part of the pancreas is INSULIN produced?
INSULIN is produced in the BETA cells of the pancreas (core of Islet)
Which part of the pancreas is GLUCAGON produced?
GLUCAGON is produced in the ALPHA cells of the pancreas (periphery islet)
What part of the pancreas is SOMATOSTATIN produced?
SOMATOSTATIN is produced in the DELTA cells of the pancreas (periphery islet)
Which Glucose Transporter is stimulated by insulin?
GLUT4 is stimulated by the hypoglycaemic action of insulin
When is GLUCAGON released?
GLUCAGON is released when blood glucose levels are LOW
When is INSULIN released?
INSULIN is released when blood glucose levels are HIGH
What does GLUCAGON do?
GLUCAGON INCREASES blood glucose levels
What does INSULIN do?
INSULIN DECREASES blood glucose levels.
Which two parts of the body are reliant on GLUT 4 for glucose uptake?
Adipose tissue and skeletal muscle are reliant on GLUT 4 for glucose uptake
WHO 1999/2006** DIABETES** DIAGNOSIS
Fasting plasma glucose?
2-h plasma glucose?
Is both needed?
WHO 1999/2006** DIABETES** DIAGNOSIS
Fasting plasma glucose: >/= 7.0mmol/l
OR
2-h plasma glucose: >/=11.1mmol/l
WHO 1999/2006 PRE DIABETES DIAGNOSIS: IMPAIRED GLUCOSE TOLERANCE
Fasting plasma glucose?
2-h plasma glucose?
Is both needed?
WHO 1999/2006 PRE DIABETES DIAGNOSIS: IMPAIRED GLUCOSE TOLERANCE
Fasting plasma glucose: < 7.0mmol
AND
2-h plasma glucose: >/= 7.8mmol to <11.1mmol/l
WHO 1999/2006 PRE DIABETES DIAGNOSIS: IMPAIRED FASTING GLUCOSE
Fasting plasma glucose?
2-h plasma glucose?
Is both needed?
WHO 1999/2006 PRE DIABETES DIAGNOSIS: IMPAIRED FASTING GLUCOSE
Fasting plasma glucose: 6.1 to 6.9mmol/l
AND
2-h plasma glucose: <7.8 mmol/l
What are symptoms of Diabetes according to WHO 1999/2006?
Symptoms of diabetes WHO 1999/2006:
* Hyperglycaemia
* Glucosuria
* Polyuria
* Polydipsia
* Fatigue and tiredness
* Weight loss
* Blurred vision
What can hyperglycaemia cause?
Hyperglycaemia can cause:
* Glucosuria (excess glucose in urine excretion can lead to weight loss)
* Polyuria (glucose in urine exerts osmotic pressure which increases urinary output leading to weight loss)
* Polydipsia (fluid loss in urine causes dehydration and increased thirst)
* Fatigue and tiredness (lack of glucose as fuel/ easiest fuel to use)
* Blurred vision (microvascular complications)
GLUT 4 TRANSPORTER
GLUT 4 TRANSPORTER
* Insulin dependent glucose transporter
* stimulates glucose uptake into muscle and adipose tissue
GESTATIONAL DIABETES DIAGNOSIS IN PREGNANCY
GESTATIONAL DIABETES DIAGNOSIS IN PREGNANCY
* Glucosuria test week 12-14
* Gestational diabetes present if:
* glycosuria 2+ or above on 1 occassion OR
* glucosuria 1+ or above on 2 or more occassions
What is somatostatin?
Somatostatin is hormone produced in the delta cells of the pancreas. It regulates insulin and glucagon secretion. It can suppress the secretion of both hormones.
What percentage of the pancreas is endocrine?
2% of the pancreas is endocrine
Which cell types are found in the islets of Langerhans?
Cell types found in the islets of Langerhans:
* beta cells: secrete insulin
* alpha cells: secrete glucagon
* delta cells: secrete somatostatin
* PP cells (F cells): secrete pancreatic polypeptide
Describe the structure of insulin
Insulin structure:
* Two polypeptide chains
* One alpha chain: 21 amino acids
* One beta chain: 30 amino acids
* Chains linked by disulphide bridges
1.Insulin is synthesized in the endoplasmic reticulum of the beta cells as the precursor __________ .
1.Insulin is synthesized in the endoplasmic reticulum of the beta cells as the precursor preproinsulin.
2 .Preproinsulin is transported to the Golgi apparatus where it is proteolytically cleaved to form __________.
2 .Preproinsulin is transported to the Golgi apparatus where it is proteolytically cleaved to form proinsulin.
What is C-peptide used for in diabetes diagnosis?
C-peptide is used to differentiate between type 1 and type 2 diabetes as it has a longer half life than insulin.
3 . Proinsulin is cleaved at two points to form the alpha and beta chains linked by disulphide bridges of ________. The remaining C peptide is stored in granules with insulin
3 . Proinsulin is cleaved at two points to form the alpha and beta chains linked by disulphide bridges of insulin. The remaining C peptide is stored in granules with insulin
Where are C-peptide and insulin stored?
C-peptide and insulin are stored in the granules.
What are the half lives of C peptide and insulin?
C peptide half life: 20-50 minutes (longer hepatic ratio extraction)
Insulin half life: 4-10 minutes
The three steps of insulin synthesis
1.Insulin is synthesized in the endoplasmic reticulum of the beta cells as the precursor preproinsulin.
2.Preproinsulin is transported to the Golgi apparatus where it is proteolytically cleaved to form proinsulin.
3. Proinsulin is cleaved at two points to form the alpha and beta chains linked by disulphide bridges of insulin. The remaining C peptide is stored in granules with insulin
(Starts with transcription and translation)
How many glucose transporters are there?
Where are they found?
There are 5 glucose transporters
1. GLUT-1 basal non insulin stimulated glucose uptake
2. GLUT-2 transports glucose into the beta cells & liver (non insulin stimulated )
3. GLUT-3 non insulin mediated uptake of glucose into the brain
4. GLUT-4 peripheral action of insulin. Enabling glucose uptake into muscle and adipose tissue (hypoglycaemic action of insulin)
5. GLUT-5 Jejunum (non insulin stimulated –fructose)
How is glucose uptake regulated in the muscle and fat cells?
Glucose uptake by muscle and fat cells is regulated by modulating the number of GLUT4 glucose transporters on the surface of cells.
How does insulin regulate glucose uptake into muscle and fat cells?
Insulin regulates glucose uptake into muscle and fat cells by recruiting membrane vesicles containing the **GLUT4 **glucose transporters from the interior of cells to the cell surface, where it allows glucose to enter cells by facultative diffusion. Once in the cytoplasm, the glucose is phosphorylated and thereby trapped inside cells
How does glucose enter the beta cells of the pancreas?
Glucose enters the beta cells of the pancreas via GLUT2..
Describe insulin release from the beta cells of the pancreas
Insulin release from the beta cells of the pancreas
1. Glucose concentration rises. Glucose enters beta pancreas cells via GLUT2.
2. Glucose is metabolized (glycolysis, link reaction, TCA cycle, the electron transport chain and oxidative phosphorylation) and ATP is formed.
3. Increases in ATP (changes to ATP/ADP ratio) causes the K ATP sensitive channel to close.
4. Closure of the K ATP sensitive channel leads to membrane depolarization
5. Membrane depolarisation causes opening of the voltage gated Ca2+ channels.
6. Opening of the voltage gated calcium channels leads to an influx of calcium into the beta cells.
7. Calcium influx triggers activation of calcium dependent phospholipid protein kinases and exocytosis of insulin.
8. C-peptide protein is released in equal amounts to insulin.
How many phases does insulin have?
Insulin has a biphasic response of 2 phases.
Which other factors influence insulin secretion?
Other factors that influence insulin secretion:
* Incretins (glucagon like peptide 1 and glucose dependent insulinotropic peptide) from gastrointestinal tract (glucose dependent)
* Innervation by the parasympathetic nervous system
* Sympathetic nervous system
What do incretins do?
Incretins act as early signals for impending glucose levels into the bloodstream
What does glucokinase do?
Glucokinase detects how much sugar is in the blood so that when the blood glucose rises, the amount of insulin produced also increases. It has a high affinity for glucose.
What does MODY stand for?
MODY stands for Maturity Onset Diabetes of the Young
Is glucose transport into the liver cells insulin dependent?
No, glucose transport into the liver cells is not insulin dependent.
What effect does insulin have on glucose uptake in the liver cells?
Although glucose uptake in the liver is not insulin dependent, insulin secretion enhances the conversion of glucose into glycogen in the liver.
Effect of insulin secretion on skeletal muscle and adipocytes
Effect of insulin secretion on skeletal muscle and adipocytes
* Insulin receptor activation causes GLUT 4 recruitment which promotes fusion of GLUT 4 containing vesicles to the plasma membrane causing a rapid increase of glucose uptake from the blood.
What is the 1st phase of insulin secretion?
1st phase of insulin secretion:
* Following a meal premade insulin containing granules are released
* Lasts for approximately 10 minutes
* Suppresses endogenous glucose production: glycogenolysis, gluconeogenesis, lipolysis
Glucose is rapidly _________ and trapped inside the cells following its facilitated passage by GLUT 4.
Glucose is rapidly phosphorylated and trapped inside the cells following its facilitated passage by GLUT 4.
What is the 2nd phase of insulin secretion?
2nd phase of insulin secretion
* longer than 1st phase
* stimulated by nutrients
* sustained until normoglycemia is restored.
* used for metabolic control post absorption
Insulin Signal Transduction Pathway in muscle/fat cells
1. Insulin binding to receptor
2. ?
3. ?
4. PDK1 binds to PIP 3 and activates protein kinase b (Akt)
Insulin Signal Transduction Pathway
1. Insulin binding to receptor leads to crossphosphorylation and activation of the insulin receptor
2. Phosphorylated sites on insulin receptor = binding sites for insulin receptor substrates
3. Phosphoinositide-3-kinase binds to sites on IRS-1 and converts PIP2 to PIP3
4. PDK1 binds to PIP 3 and phosphorylates and activates protein kinase b (Akt)
What does activated protein kinase b (akt) do?
Activated protein kinase b (Akt/PKB):
* stimulates movement of GLUT 4 to the cell membrane to increase glucose uptake
* Activates glycogen synthase by inactivating glycogen synthase kinase 3 (glycogenesis)
* Has an effect on the MAP kinase pathway (cell proliferation, differentiation, Mitosis, Apoptosis)
* Inhibits gluconeogenesis
Is activated protein kinase b (Akt/PKB) located on the cell membrane?
No Akt/PKB is not membrane bound, it can move anywhere in the cell
What is the effect of insulin on liver cells?
In the liver cells, insulin stimulates conversion of glucose to glycogen.
The more insulin present in the liver initiates more PKB (Akt) activation stimulating ________ synthesis
The more insulin present in the liver initiates more PKB (Akt) activation stimulating ** glycogen synthesis**.
Insulin effects the glucose** ** in hepatocytes.
Insulin effects the glucose concentration gradient in hepatocytes.
What is the effect of insulin on carbohydrate metabolism?
Insulin effect on carbohydrate metabolism:
* Increased glucose uptake via GLUT 4 recruitment (muscle and fat cells)
* Glycerol production in adipose tissue for triglyceride synthesis
* Glycogen synthesis in muscle and liver cells
* Inhibition of glycogenolysis and gluconeogenesis
Why are most Type 1 diabetics slender?
Type 1 diabetics are usually slender because the absence of insulin prevents the storage processes of fat synthesis and glycogenesis etc.
What is the effect of insulin on protein metabolism?
Effect of insulin on protein metabolism:
* Protein synthesis is stimulated due to amino acid uptake
* Amino acid breakdown is inhibited
What is the effect of insulin on fat metabolism?
Effect of insulin on fat metabolism:
* Promotion of lipogenesis from glycerol derived glycerol
* Stimulates fatty acid transporter translocation via Akt/PKB
* Inhibits lipolysis
* Promotes fatty acid synthesis via increased acetyl CoA carboxylase activity
What does insulins anabolic/ removal of glucose from the blood do?
Insulins anabolic influence/ removal of glucose from the blood:
* Lowers blood glucose levels
* Lowers free fatty acid levels
* And essential amino acids
*
What causes Type 1 diabetes?
Type 1 diabetes is caused by an immune response. Something causes an attack on the beta cells of the pancreas.
There are genetic and environmental factors involved
Do Type 1 diabetics produce insulin?
Type 1 diabetics do not produce insulin and are dependent on insulin treatments for survival.
Which gene might be linked to Type 1 diabetes?
There might be a link between type 1 diabetes and HLA (human leucocyte antigen) gene system on chromosome 6.
Diabetes may be caused by an ________________ immune response to a viral or bacterial infection.
Diabetes may be caused by an** inappropriate **immune response to a viral or bacterial infection.
What does HLA (human leucocyte antigen) gene system usually do? What might it do in Type 1 diabetes.
HLA (human leucocyte antigen) gene system helps the body to recognise self or non-self cells. In Type 1 diabetes it may be linked to the autoimmune reaction of attack on the beta cells
Which environmental factors may cause Type 1 diabetes?
Environmental factors that may cause Type 1 diabetes:
* Drugs and chemicals/pollutants
* Nutritional intake
* Viruses, mumps, rubella, cytomegalovirus.
These could exert a toxic effect on the b-cells
Trigger an autoimmune reaction against the b-cells
Damage the b- cells so as to increase their susceptibility to damage.
Type 1 diabetes as an autoimmune disease
CD4+ & CD8+ T-cells and macrophages destruction of the β cells .
Specifically targets the β cells – spares other pancreatic cell subsets.
What physical symptoms might you see in Type 1 diabetes?
Physical symptoms in Type 1 diabetes:
* Vitiligo
* Eruptive xanthomatosis
* Sclerodermadiabeticorum ( & Type 2)
* Acanthosis nigricans (& Type 2)
What percentage of functionality loss of the beta cells must be loss before hyperglycaemia occurs in Type 1 diabetes?
80-90% of the function of the insulin – secreting beta cells in the islets must be lost before hyperglycaemia occurs.
What is the honeymoon period in Type 1 diabetes?
Type 1 diabetes honeymoon period:
The “honeymoon period” is a phase that some people with type 1 diabetes experience shortly after being diagnosed. During this time, a person with diabetes seems to get better and may only need minimal amounts of insulin. Some people even experience normal or near-normal blood sugar levels without taking insulin.
Things then get worse.
In Type 1 diabetes there is a ________ of insulin but an ________ of glucagon.
In Type 1 diabetes there is a **lack **of insulin but a lack of glucagon.
In Type 1 diabetes why is blood glucose raised further?
In type 1 diabetes blood glucose is raised further because of excess glucagon which stimulates catabolic processes which release glucose into the bloodstream and promote glucose synthesis from non-carbohydrate stores,
What are the classic presenting symptoms of Type 1 diabetes?
Classic presenting symptoms of Type 1 diabetes
* Glucosuria - excess glucose in the urine
* Polyuria – glucose in the urine exerts osmotic pressure in the filtrate resulting in a large quantity of urine to be excreted.
* Polydipsia – fluid loss through the urine draws water from the cells leading to dehydration and increased thirst.
* Polyphagia – lack of nutrients to the cells stimulates appetite.
* Ketonuria. Ketones in the urine
Diagnosis is confirmed with blood glucose testing
What does insulin deficiency cause?
Insulin deficiency causes:
* Increased proteolysis
* Increased lipolysis> ketogenesis> acidosis> fruity breath> kaussmal breathing
* Reduced glucose uptake > hyperglycaemia> osmotic diuresis> electrolyte imbalance OR polyuria/polydipsia>dehydration
Glucosuria
- Glucosuria - excess glucose in the urine
Polyuria
Polyuria – glucose in the urine exerts osmotic pressure in the filtrate resulting in a large quantity of urine to be excreted.
Polydipsia
- Polydipsia – fluid loss through the urine draws water from the cells leading to dehydration and increased thirst.
Polyphagia
- Polyphagia – lack of nutrients to the cells stimulates appetite.
Ketonuria
- Ketonuria. Ketones in the urine
T2D peak of onset in developed and developing countries
Peak of onset in developed countries 60-70 years.
Developing countries peak of onset is now 40-45 years.
What is insulin resistance strongly associated with?
Insulin resistance is strongly associated with obesity and physical inactivity
What is the effect of increased mass of stored triglyceride on insulin?
Increased mass of stored triglyceride leads to large adipocytes that are resistant to the ability of insulin to supress lipolysis, resulting in increased circulating levels of NEFA and glycerol which aggravate insulin resistance
What are the two main metabolic defects in T2D?
Impaired insulin secretion
Insulin resistance (A given concentration of insulin produces a less than normal biological response)
What are the classic symptoms of Type 2 diabetes?
Classic symptoms of Type 2 diabetes
* Polydipsia, polyuria, polyphagia,.
* Overweight, dyslipidemic, hyperinsulinaemia.
* Fatigue
* Pruritus, itching,
* Recurrent infections, thrush
* Visual changes
* Paresthesias (abnormal sensations, tingling)
What are the risk factors of T2D?
T2D risk factors
Non-modifiable
History of gestational diabetes
Race/Ethnicity (South Asians 6x more likely, Africans 3x more likely)
Age over 45 years
Family history of diabetes
Modifiable
Physical inactivity
High body fat or weight
High blood pressure
High cholesterol
Describe insulin resistance
Insulin resistance:
* Defect in binding to the insulin receptor
* Defect in the insulin receptor kinase activity
* GLUT4 coding sequence and GLUT4 protein levels normal BUT insulin stimulated translocation of GLUT4 is impaired
* Reduced or absent first phase insulin response
* Delayed response to ingestion of meals
* Alterations in rapid pulse and oscillations of insulin secretion
* Defective β cell proinsulin processing ↑ levels of plasma proinsulin and partially processed proinsulin molecules compared to insulin
* Reduced second phase response
* Fasting hyperinsulinaemia
Describe the pathophysiology of T2D
Genetic factors – increase susceptibility to develop glucose intolerance
Ethnicity – 6x (south Asians), 3x (African)
Familial – 10% sibling / 30% both parents/ 40% twins
Non- genetic environmental factors affect insulin secretion and insulin action
obesity, aging, sedentary lifestyle.
The ‘thrifty phenotype’ hypothesis.
Progressive deterioration of -cell function
Thrifty phenotype –hypothesis suggests that in the past times of famine caused selective pressures for a genotype and leads to efficient fat storage during times of abundance. low birth weight and the later development of diabetes. Links foetal malnutrition with impaired beta cell development and insulin resistance in adulthood.
B-cell function is already reduced to 50% at diagnosis and continues to decline even after therapy.
The thrifty phenotype hypothesis proposes that the epidemiological associations between poor fetal and infant growth and the subsequent development of type 2 diabetes and the metabolic syndrome result from the effects of poor nutrition in early life, which produces permanent changes in glucose-insulin metabolism. These changes include reduced capacity for insulin secretion and insulin resistance which, combined with effects of obesity, ageing and physical inactivity, are the most important factors in determining type 2 diabetes. Since the hypothesis was proposed, many studies world-wide have confirmed the initial epidemiological evidence, although the strength of the relationships has varied from one study to another. The relationship with insulin resistance is clear at all ages studied. Less clear is the relationship with insulin secretion. The relative contribution of genes and environment to these relationships remains a matter of debate. The contributions of maternal hyperglycaemia and the trajectory of postnatal growth need to be clarified.
What are the complications of diabetes?
Complications of diabetes
* Microvascular complications tend to manifest 10-20 years after diagnosis
* Frequency of CHD, stroke and peripheral vascular disease are 2-4 x higher than general population.
* CVD most common about 75% of death type 2 diabetes.
* Pathology of atheroma identical to non diabetics.
* Retinopathy: Blurred vision, cataracts, glaucoma
* Nephropathy: 20-40% Type 1 patients rarer in Type 2
* Renal hypertrophy caused by raised glomerular filtration rate.
* Neuropathy:
Acute (reversible) – ‘Burning foot’
Peripheral – Touch, pain and temperature
Autonomic - orthostatic hypotension, nausea and constipation, incontinence and erectile dysfunction.
*
Damage of the large blood vessels. Occurs as a result of diabetes and
raised cholesterol
high blood pressure
Smoking
Presented
Heart (angina/heart attacks/MI)
Circulation (atherosclerosis)
Brain (stoke/cerebrovascular disease)
