Diabetes Flashcards
Full name of diabetes
Give meaning and reason for name
Diabetes mellitus
“Siphon of honey” - one feature of the disease is passing large volumes of urine containing glucose (when there are high levels of blood glucose)
What is diabetes
A disease in which blood glucose concentration is inappropriately raised
What are normal blood glucose levels
4mM(fasting) - 7mM (fed)
Does insulin affect all tissues in the same way
No
It is required for efficient uptake of glucose in muscle and fat but not in liver or brain, which respond to it in other ways
Insulin is a ____ by function and a ____ by structure
Hormone
Protein
What is the % of diabetics who are type one
5%
What causes type 1 diabetes
Environmental: could be a virus or chemical
Genetic: several genes have been identified which can predispose or protect
How might type 1 diabetes be cured
Transplant of islets or stem cells
Vaccine?
How much of diabetics are type 2
90%
What are the genetic and environmental components that affect type 2 diabetes
Genetic: no simple inheritance: different genes might contribute, runs in families
Environmental: low birth weight and adult obesity are major risk factors
Treatment for type 2 diabetes?
Mild: lifestyle (diet and exercise)
Moderate: drugs that stimulate insulin secretion or improve insulin sensitivity
Severe: insulin injection
What kind of drugs increase insulin secretion
Sulphonylureas
What kind of drugs improve insulin sensitivity?
Thiazolidinediones
What are the rarer forms of diabetes
MODY (mature onset diabetes of the young)
Severe insulin resistance (mutation in insulin receptor)
Gestational diabetes (pregnancy associated hormone disturbance, affecting insulin)
Secondary diabetes (as a consequence of a pancreatic disease or hormone disturbance)
What happens in the short term for type 1 diabetes generally
Glucose uptake into muscle and fat is impaired, causing hyperglycaemia
Glucose spills over into urine, requiring water for excretion
Body fat and protein are broken down as alternative fuels
Production of ketoacids from fats is increased
What happens if food intake doesn’t match insulin therapy
Hypoglycaemia, leading to trembling, sweating and potentially a coma (due to a lack of glucose to the brain)
Long term complications of diabetes
Micro vascular: eyes and kidney
Neuropathy: particularly deer
Macro vascular: increased risk of stroke and heart attack
How many amino acids does insulin have? Is every one necessary?
Briefly describe its structure
51
No
2 polypeptide chains linked by disulphide bonds between C residues
Who discovered insulin’s primary structure
Sanger in Cambridge in 1955
What is glucagon
A polypeptide, produced by alpha cells in pancreatic islets of Langerhans
How does [insulin] compare to [glucose]
[insulin]= 0.1-1nM [glucose] = 5-10 mM
In insulin anabolic?
Yes
How does insulin affect muscle
Increases glucose uptake
Increases conversion of glucose to glycogen
Increases protein synthesis
Decreases proteolysis
How does insulin affect fat
Increases glucose uptake
Increases lipogenesis
Decreases lipolysis
Increases protein synthesis
How does insulin affect
The Liver
No effect on glucose uptake
Increases conversion of glucose into glycogen and lipid
Decreases gluconeogenesis and glycogenolysis
How does insulin affect the CNS
No effect on glucose uptake or metabolism
Suppressed appetite
Promotes fertility
How does insulin affect pancreatic beta cells
Promotes insulin synthesis and secretion
Promotes proliferation
What subcellular compartments does insulin act on
Stimulation of glucose uptake involves trafficking vesicles to plasma membranes
Stimulations of glycogen synthesis involves effects in cytosolic enzymes
Stimulation of lipogenesis involves effects on mitochondrial and cytosolic enzymes
Inhibition of gluconeogenesis involves effects in gene transcription in the nucleus
3 reasons all cells need a constant supply on energy
Biosynthetic reactions in maintenance and division
Maintain correct ionic and chemical balance of intracelleular environment
Specialised functions eg muscle contraction
How do mammalian cells obtain energy from derivatives of food
Oxidation
What does an ATP molecule contain
A heterocyclic base, ribose and 3 phosphates
How many pathways exist in mammals to convert fat into glucose
None
When are catabolic pathways active
Always
May be accelerated to meet energy demand
When are storage pathways most active?
Fed state, whereas mobilisation occurs during fasting or exercise
When does lipogenesis occur
Fed state
When does gluconeogenesis mainly occur
Fasting
What are the main regulators and consumers of the body’s fuel supply
Regulators: liver and fat
Consumers: Muscle and Brain
What metabolic processes occur mainly in the liver
Lipogenesis
Gluconeogenesis
Ketogenesis
Where does lipogenesis occur
Liver
Fat
What does insulin do in fed state
Promotes uptake and storage of products of digestion by muscle and fat
What does glucagon do in fasting state
Promotes gluconeogenesis (in liver) and lipolysis in fat
What does Adrenalin do I’m stressed state
Promotes glycogenolysis in muscle and lipolysis in fat
Where is insulin secreted and what is it originally
Pancreatic β cells
A larger precursor, proinsulin, which is then directed into vesicles and cleaved by proteases
What happens to insulin after proinsulin is cleaved
Remains stored in vesicles until the cell receives signals to secrete insulin. Excretion occurs via exocytosis
What conc of glucose is required to stimulate insulin release
Above 5mM
What does glucokinase do
Converts glucose into glucose-6-phosphate
It also acts as a glucose sensor, beginning the process of glucose metabolism
How does ATP affect β-cells
How does this relate to drugs
Regulates their ion channels
Drugs to stimulate insulin secretion act on the same channels
How does insulin act to lower blood glucose in muscle
Stimulates glucose uptake and conversion to glycogen
How does insulin act to lower blood glucose in fat
Stimulates glucose uptake and conversion into triacylglycerol
How does insulin act to lower blood glucose in liver
Stimulates glycogen synthesis and inhibits glucose production
How does insulin act to lower blood glucose in brain
Suppresses appetite and may influence centres controlling peripheral glucose utilisation
How do insulin receptors work
Extra cellular part of receptor has a special recognition site to bind insulin.
Intracellular part is a protein tyrosine kinase which is activated upon bonding, initiating a signalling cascade
What are the different ways protein phosphorylation is a regulatory mechanism
Simultaneous and coordinated control of several enzymes
Activation or inhibition
Distinct kinases can induce phosphorylation at different sites on same protein thus integrating the effects of different primary signals
How many times does the glucose transporter polypeptide span the membrane
12 time’s, forming a transport pore through which glucose can enter by diffusion
What does stimulation of glycogen synthesis involve
De phosphorylation of glycogen synthase
How does a decrease in the number of insulin receptors affect someone
Meh unlikely to be of great importance
Subtle changes in the level and activity of proteins are more important
Give BMI classifications for
Normal
Overweight
Obese
Normal: 20-25
Overweight: 26-30
Obese: >30
True or false:
All type 2 diabetics are obese and most obese people are diabetic
False:
Most T2 diabetics are obese but most obese people are not diabetic
How does risk of diabetes increase with BMI for men and women
Women: 5x at 25; 30x at 30, 100x at 35
Men; 2x at 25, 25x at 30, 40x at 35
How does obesity increase chance of T2 diabetes
Obesity causes insulin resistance
What is the lipotoxicity theory for how obesity causes insulin resistance
Lipid overload: increases flux of FFA and TAG leads to lipid accumulation, antagonising insulin signalling by lipid related protein serine kinases
Is T2 Diabetes a disorder of metabolism of lipids or carbohydrates?
Both
Adipose tissue is increasingly seen as playing a central role in disease progression
How does Type 2 diabetes ensue
Insulin sensitivity decreases with age and in obesity so insulin production increases to compensate for this.
Insulin secretion is later impaired by hyperglycaemia and hyperlipidaemia resulting from insulin resistance
Type 2 diabetes occurs when pancreas can no longer cope with The increased demand
What happens in the absence of effective insulin action
Muscle is not able to take up sufficient glucose to satisfy energy requirements
Breakdown of fat and protein is increased as they are no longer being inhibited
What happens during persistent elevated blood glucose
Renal threshold is exceeded and glucose is lost in urine
What happens in untreated extreme T1 diabetes
Fat breakdown exceeds capacity of tissues to utilise fatty acids and ketone bodies are formed leading to acidosis
Why are sub classes important
Treatment maybe effective for one sub group but not another’s
Before modern medicine what did disease sub division rely on
Eg?
Clinical observation
Diabetes used to be subdivided into insipidus and mellitus depending on the urine
What did Himsworth propose in 1936
Diabetes mellitus had 2 sub types :
Insulin deficiency and insulin resistance
What made measuring insulin in blood possible
Radioimmunoassay technology
What is the typical age of onset for type 1 and 2 diabetes
1: early age
2: 40-70
How does type 2 diabetes develop
Slowly and with variable severity
May be asymptomatic for years
Is type 2 diabetes a specific diagnosis
No it is more of a clinical label (to aid management and decision making)
What is ketosis prone diabetes
Observed in African American population and in sub Sahara
Male predominant
Presents acutely with metabolic decompensation and diabetic ketoacidosis
Requires insulin acutely but β cells recover and insulin isn’t needed in the long run
What is MODY
Maturity onset diabetes of the Young
A heterogeneous group of disorders that result in β cell dysfunction
How many genes are currently know to be associated with MODY
Which 5 are most common
Why is this important
9
HNF-4a Glucokinase HNF-1a IPF-1 HNF-1b
To Inform prognosis and treatment
Does diabetes usually appear in the first 3 months of life
No
Patients with this form have previously been treated with insulin for life
What can neonatal diabetes be caused by
Mutation in Kir6.2 subunit of ATP sensitive K+ channel which mediates glucose stimulated insulin secretion in the β cell
What can mitochondrial disease be caused by
Mutations is nuclear DNA or in mitochondrial DNA
What can a mutation in m.3243 cause
What is the mutation
MIDD and MELAS syndrome
A>G
What is MIDD
Maternally Inherited Diabetes and Deafness
What is MELAS syndrome
Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke like episodes
What is metformin
An oral hypoglycaemic agent
4 ways to further stratify disease
Moving from studying rare genetic mutations to common polymorphisms
Stratification by response to medication
Stratification by response to lifestyle
Aetiological Stratification on the basis of gene-environment interaction
What might response to metformin by affected by
Genetic variation at the ATM locus
What is the strongest common locus variant for type 2 diabetes
TCF7L2
CCK:
a) structure
b) where is it secreted
c) what does it act on and what is the effect (3)
a) a mixture of peptides, where the octapeptide is the most active
b) secreted in duodenum and jejunum when exposed to protein and fat digestion products by I cells
c) acts on gall bladder, stimulating contraction; acts on pancreases to stimulate release of enzymes; acts on Vagal afferents to medulla oblongata causing satiety
Ghrelin:
a) structure
b) where is it secreted
c) what does it act on and what is the effect (2)
a) 28 amino acids
b) secreted by stomach endocrine cells in response to fasting
c) acts on hypothalamus to stimulate feeding; counteracts effects of leptin and PYY-3-36
Neuropeptide Y (NPY)
a) structure
b) where is it secreted
c) what does it act on and what is the effect (3)
a) 36 amino acids
b) secreted by neurons in hypothalamus
c) Potent feeding stimulant and causes increased storage of ingested food as fat; also blocks transmission of pain signals to the brain
PYY 3-36
a) structure
b) where is it secreted
c) what does it act on and what is the effect (3)
a) 34 αα with 21 residues identical time sequence in NPY
b) released by intestinal cells after meals, amount secreted increases with calories ingested
c) acts on:
•hypothalamus to suppress appetite
• pancreas to regulate exocrine secretion
• gall bladder to stimulate contraction
Which of the following works tastes to suppress appetite: CCK leptin PYY (Fastest to slowest)
CCK>PYY> leptin
What are IL6 and TNF
How do these affect obesity related diseases
Inflammatory factors (cytokines) secreted by adipose
These may contribute to disease: without TNF, might develop obesity but not insulin resistance or Type II diabetes
How do the levels of adiponectin vary
Levels fall as fat mass increases
What is BMR
The metabolic rate of a resting fasted adults in a Thermo neutral environment
What are the proportions of oxygen consumption of the BMR
65%= mitochondrial production of ATP 20%= intrinsic H+ leakiness in mitochondria
The rest are non mitochondria based
What are the proportions of ATP expenditure
Na/K pump: 25% Protein synthesis: 25% Ca+ pump: 5% Actinomysin ATPase: 5% Gluconeogenesis: 7% Urea formation: 2% DNA/ RNA synthesis: 30-40%
How efficient is obviously phosphorylation in terms of ATP production
70%
What is DIT
Diet induced thermogenesis
The increase in energy expenditure above basal fasting level
————————————-
Energy content of ingested food
What happens in malignant hyperthermia
Calcium leakage from the SR and increased activity of ATP calcium pumps to return it
There is a consequent rise in oxygen consumption and CO2 output leaving to acidosis, tachycardia and heat generation
Give a simplified summary of the formation and release of thyroid hormones
Iodide ions are concentrated by the thyroid gland using the Na/I co-transporter
Synthesis occurs in The space outside follicle cells
Eight peroxidase complex uses hydrogen peroxide to conjugate iodide to tyrosine residues of the protein thyroglobulin
Thyroglobulin enters the cell by endocytosis and is broken down into secondary lysosomes to release T4 and T3
How much of T3 and T4 are dissolved in blood
V little
99% are protein bound
What is the effect of thyroid hormones on energy metabolism
They stimulate metabolic rate by increasing expression of genes that include proteins involved in oxidative metabolism and thermogenesis
How does T3 affect the expression of genes
T3 easily enters cells due to being lipid soluble and attaches to a receptor protein in the nucleus and also bunds to the retinoids X receptor
The resulting heterodimer which binds to DNA sequences in promoter regions
What is myxoedema?
Hypothyroidism
Which thyroid problem causes facial swelling
Hypothyroidism
Due to a build up of glycoproteins
Why does a goiter form in hypothyroidism
T4 normally inhibits TSH secretion so TSH rises when T4 is low and stimulates growth of the thyroid gland
What is diabetes
Dis regulation of blood glucose
Difference between symptom and sign
Symptom: subjectively described
Sign: objective
What is diabetes insipidus
Too little ADH/ insensitive to ADH
What causes XS urination in diabetes
Increases osmotic pressure in tubules due to excess glucose
This increased osmotic pressure leads to micro-vascular damages which can lead to blindness etc
Are you born with type 1 diabetes
No
Do you get comas for hypoglycaemia or hyperglycaemia
Both
Hypo is more unpleasant as the body shuts down and nervous control is lost
What causes a coma in ketosis
Low pH in the brain
What does genetic determinism mean
Their genes mean they WILL get the disease
What is HBA1c
Tests levels of glycated Hb
Which GLUT receptor is insulin dependent
GLUT4
In 1 person how many genes cause MODY
1 gene mutation
