CASE 6 Flashcards
what is diabetes mellitus?
a syndrome of impaired carbohydrate, fat and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin
what are the 2 types of diabetes and what are they caused by?
- t1d = caused by lack of insulin secretion
- t2d = decreased sensitivity of target tissues to the metabolic effect of insulin aka. insulin resistance
what is blood glucsoe conc like in diabetes?
elevated as there is a decrease in glucose uptake
how does the utilisation of glucose/fats/protein change in diabetes?
cell utilisation of glucose falls increasingly lower, whereas utilisation of fats and protein increases
what are the most common signs and symptoms of diabetes?
- polyuria
- polydipsia
- polyphagia (increased hunger)
- xerostomia (dry mouth)
- weight loss
- fatigue
what leads to t1d?
injury to beta cells of the pancreas or diseases that impair insulin producton
what % of the islet of langerhans need to be destroyed to develop t1d?
90%
t1d may develop very abruptly, over a period of a few days or weeks, with what 3 principle sequelae?
- increased blood glucose
- increased utilisation of fats for energy for formation of cholesterol by the liver
- depletion of the body’s proteins for use of energy within the cells themselves
how does increased glucose in urine lead to dehydration?
partly because glucsoe does not diffuse easily throguh the pores of the CM, and the INCREASED OSMOTIC PRESSURE in the ECF causes osmotic transfer of water out of the cells
how does the loss of glucsoe in urine cause osmotic diuresis?
the osmotic effect of glucose in the renal tubules greatly decreases tubular reabsoprtion of fluid — the overall effect is massive loss of fluid in urine (due to glucsoe drawing water into the urine), causing dehydration of the ECF, which in turn causes compensatory dehydration of the ICF
what things do chronic high glucose concentrations increase the risk for?
- heart attack
- stroke
- end stage kidney disease
- retinopathy
- ischemia and gangrene of the limbs
- peripheral neuropathy
- autonomic NS dysfunction
_______ secondary to renal injury, and _______ secondary to abnormal lipid metabolism often develop in patients with diabetes and amplify the tissue damage caused by the elevated glucsoe
- hypertension
- atherosclerosis
the shift from carbohydrate to fat metabolism in diabetes increase the release of what? what is the result?
- release of keto acids such as acetoacetic acid and b-hydroxybutyric acid, into the plasma more rapidly than they can be taken up and oxidised by the tissue cells
- as a result patient can develop severe metabolic acidosis from the excess keto acids, which in association with dehydration due to excessive urine formation, can cause severe acidosis
what can severe acidosis rapidly lead to unless immediately treated with large amounts of insulin?
diabetic coma (pH < 7)
what does the excess fat utilisation in the liver over a long period of time cause?
large amounts of cholesterol in the circulating blood and increased deposition of cholesterol in the arterial walls, causing arteriosclerosis and other vascular lesions
why can rapid weight loss and asthenia (lack of energy) despite eating large amounts of food (polyphagia) occur in diabetes?
body’s failure to use glucsoe for energy leads to increased utilisation and decreased storayfe of proteins as well as fat
what is the most important risk factor for t2d?
obesity
what are risk factors for t2d?
- age >40 (>25 for south asians)
- genetics (FH)
- ethnicity
- obesity
- insulin resistance (metabolic syndrome)
- PCOS
- excess formation of glucocorticoids (cushing’s syndrome)
- excess formation of growth hormone (acromegaly)
what type of diabetes is associated with increased plasma insulin conc (hyperinsulinemia)?
2
why does hyperinsulinemia occur in t2d?
compensatory response by the pancreatic beta cells for diminished sensitivity of target tissues to the metabolic effects of insulin — insulin resistance
the decrease in insulin sensitivity imparts carbohydrate utilisation and storage, raising blood glucsoe and stimulating a compensatory increase in insulin secretion
what are reasons for insulin resistance?
- possibly fewer insulin receptor is in obese
- impaired insulin signalling appears to be closely related to toxic effects of lipid accumulation in tissues (obesity) — TNFa
- gene mutations that encode dysfunctional intracellular proteins involved in this signalling
what are features of metabolic syndrome?
- obesity — esp accumulation of adipose tissue in the abdominal cavity and the visceral organs
- insulin resistance — leading to increased blood glucose conc
- fasting hyperglycaemia
- lipid abnormalities such as increased blood triglycerides (cause atherosclerosis) and decreased blood HDL-cholesterol
- hypertension
what happens to beta cells in layer stages of t2d?
become exhausted — unable to produce enough insulin to prevent more severe hyperglycaemia, esp after the person ingests a carb rich mean
what are likely to occur in a state of severe hypoglycaemia?
colonic seizures and loss of consciousness
what is the treatment for hypoglycaemic shock or coma?
- immediate intravenous administration of large quantities of glucose (usually brings the patient out of shock within a minute or more)
- administration of glucagon can cause glycogenolysis in the liver and thereby increase the blood glucose level extremely rapidly
if treatment is not effective immediately, permanent damage to the neuronal cells of the CNS often occurs
what investigations are done for diagnosis of diabetes mellitus?
- blood glucose
- urine test for proteins and glucose (and ketones)
- HbA1c to identify average plasma conc over prolonged periods of time
- BP
- blood fats
- arterial blood gases
- blood pH
what does protein in the urine indicate?
diabetic kidney disease
what do ketones in urines indicate?
ketoacidosis
describe the acetone breath test
- small quantities of acetoacetic acid in the blood, which increase greatly in severe diabetes, are converted to acetone
- this is volatile and vaporised in the air
- a diagnosis of t1d can be made by smelling acetone on the breath of the patient
- also, keto acids can be detected in urine, and their quantisation aids in determine the severity of the diabetes
how does keto acid production vary with the severity of t2d?
- in the early stages, keto acids are usually not produced in excess amounts
- however, when insulin resistance becomes very severe and there is greatly increased utilisation of fats for energy, keto acids are then produced in persons with t2d
what is the HbA1c target for most people with diabetes?
<48 mmol/mol
what is measured in the blood test for diabetes?
- glucose
- acetoacetate and acetone — testing for ketoacidosis
- Na+
- K+
- HCO3-
- creatine
- urea
- osmolality = conc of solution
- total protein
what might Na+ levels be like in diabetes and why?
elevated = hypernatremia
- this occurs due to osmotic diuresis in hyperglycaemia
- Na+ moves out of cells, bringing water with them
what might K+ levels be like in diabetes and why?
elevated = hyperkalaemia
- usually as a result of ketoacidosis
- this is because the body tries to take H+ ions out of the blood by exchanging them for K+ ions, via the H+/K+ exchanger
what might creatinine levels be like in diabetes and why?
elevated due to the breakdown of muscles due to the lack of insulin effect (protein cant be stored)
what might urea levels be like in diabetes and why?
increased as more protein is broken down, more ammonia (a product of deamination) needs to be excreted from the body
what might osmolality levels be like in diabetes and why?
elevated due to the presence of increased glucsoe in the blood, thus concentrating the blood. the body secretes ADH to try and reabsorb more water in the kidneys
what might total protein levels be like in diabetes and why?
elevated because of the breakdown of muscle, thus the breakdown amino acids enter the blood
what is the aim of treatment in t1d?
to administer enough insulin so that the patient will habe carbohydrate, fat and protein metabolism that is as normal as possible
what is the normal treatment of someone with severe t1d?
- a single dose of a longer-carting insulin each day to increase overall carb metabolism thoughout the day
- then additional quantities of regular insulin throughout the day at times when the blood glucose levels tends to rise too high, such as mealtimes
what is the 1st line treatment in t2d?
dieting and excercising
what drugs increase insulin sensitivity?
metformin and thiazoldinediones
what drugs stimulate increased production of insulin by the pancreas?
sulphonylureas eg. gliclazide
have i done ADH system
ikd
describe the structure of insulin
consists of two polypeptide chains, an A chain and a B chain, covalently linked by two inter-chain disulfide bridges. There is a third, intra-chain disulfide bridge.
in insulin synthesis, firstly the insulin mRNA is translated as a single chain precursor called what?
preproinsulin
what happens to preproinsulin?
a single peptide is removed at the N-terminus during insertion at the endoplasmic reticulum — this generates proinsulin
what happens in the endoplasmic reticulum to proinsulin?
endopeptidases excise a connecting peptide (c-peptide) between the A and B chains — this breaks the single-chain into 2 strands (A and B) that are held together by disulfide bridges ie. this generates the mature form of insulin
equimolar amounts of insulin and __________ are packaged in the ____________ into storage vesicles which accumulate in the cytoplasm
- free c-peptide
- golgi apparatus
glucose is transproted into the beta cell by facilitated diffusion throguh what channels?
GLUT2
what does the rise in conc of glucose in the beta cell lead to?
membrane depolarisation of ATP-sensitive K+ channels, opening Ca++ channels
an increase in intracellular Ca+ triggers insulin release by what 2 stage process?
Margination: the process by which insulin storage vesicles move to the cell surface.
Exocytosis: This is fusion of the vesicle membrane with the plasma membrane, with release of the vesicle’s entire contents
describe the biphasic secretion of insulin
Pulsatile release (rapid onset): Short term blood glucose control: clearing absorbed nutrients from the blood following a meal.
Protracted release (longer): Long term insulin release for glucose uptake e.g. for cell growth, cell division, stimulating protein synthesis and DNA replication.
in muscle and liver, insulin increases _________ and decreases __________
increases glycogenesis and decreases glycogenolysis
what does insulin decrease in the liver?
gluconeogenesis
insulin causes increased what in liver and adipose tissue?
glycolysis
insulin decreases the breakdown of what in the liver?
amino acids
increased ________ and _________- in muscle, liver and adipose tissue due to insulin
increased amino acid uptake and protein synthesis
is lipolysis increased or decreased due to insulin?
decreased
lipogenesis due to insulin?
increased
what stimulate insulin secretion?
GI tract hormones, ACh
what inhibit insulin secretion?
adrenaline and noradrenaline
what is somatostatin produced by?
the D cells of the stomach and duodenum, and the δ cells of the islets of Langerhans of the pancreas
somatostatin secretion is stimulated by what?
the presence of glucsoe, amino acids and glucagon-like-peptide-1
what is the primary role of somatostatin in gastric physiology?
inhibit btoh gastrin release and parietal cell acid secretion
in the stomach, where are D cells found?
near the base of the oxyntic glands, the predominant gland type within the body and fundus of the stomach
describe the direct pathway of somatostatin in inhibiting gastric acid secretion
- when released into the stomach, somatostatin binds to a a-1 G-protein coupled receptor on the basolateral membrane of the parietal cell
- this binding leads to the inhibition of adenylyl cyclase, antagonising the stimulatory effect of histamine
- thus inhibiting gastric acid secretion by parietal cells
___________ and ________ are both examples of secretagogues which are substances that cause another substance to be secreted and due to this function, somatostatin can inhibit gastric acid secretion.
histamine and gastrin
in the corpus of the stomach, D cells release somatostatin to do what?
inhibit the release of histamine from the enterochromaffin-like cells (ECL cells)
in the antrum of the stomach, D cells release somatostatin to do what?
to inhibit the release of gastrin from G cells
what is somatostatin secreted by in the pancreas?
δ-cells
when is the glucsoe tolerace test most commonly used?
gestational diabetes
what lowers HbA1c results? (non-diabetes related)
- sickle cell anaemia
- GP6D deficiency
- hereditary spherocytosis
- haemodialysis
what increases HbA1c? (non-diabetes related)
- vitamin B12/folic acid deficiency
- iron deficiency anaemia
- splenectomy
what does somatostatin do in the pancreas?
acts as a powerful inhibitor of glucagon and insulin secretion from the α- and β-cells, respectively
what stimulates somatostatin secretion via G proteins?
glucose
how do high blood glucose levels cause somatostatin release from delta cells in the pancreas?
- when blood glucose concentrations are high, activation of cellular receptors causes the closure of ATP-sensitive K+ channels, initiating membrnae depolarisation and increasing SS release from delta cells
how does somatostatin suppress pancreatic exocrine secretions?
through the inhibition of cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion
somatostatin effects on: gastrin release
decreases gastrin release leading to reduced gastric acid
somatostatin effects on: fluid absoprtion
increased
somatostatin effects on: smooth muscle contraction
increases
somatostatin effects on: insulin and glucagon
paracrine inhibition of insulin and glucagon secretion from α and β-cells of the Islets of Langerhans
somatostatin effects on: bile flow
decreases
somatostatin effects on: blood glucose conc
decreases
what is somatostatin a potent inhibitor of (nervous system)?
growth hormone
sometimes referred to as Growth Hormone Inhibiting Hormone (GHIH)
summary of neurological effects of somatostatin
- Inhibits secretion of growth hormone from the anterior pituitary
- Inhibits secretion of thyroid-stimulating hormone from the anterior pituitary
high dose of glucose, which under normal conditions should lead to inhibition of _______________ through the release of somatostatin
growth hormone
which antidiabetic drugs reduce the risk of heart failure?
SGLT2 inhibitors
which antidiabetic drugs increase the risk of UTIs?
SGLT2 inhibitors
what does metformin do?
increases insulin sensitivity, decreases hepatic gluconeogenesis
metformin main side effects
- GI upset
- lactic acidosis
metformin cannot be used in patients with an eGFR of what?
<30ml/min
what do sulfonylureas do?
stimulate pancreatic beta cells to secrete insulin
main side effects of sulfonylureas eg. gliclazide
- hypoglycaemia
- weight gain
- hyponatraemia
thiazolidinediones MoA
activate PPAR-y receptor in adipocytes to promote adipogenesis and fatty acid uptake
what is the only currently available thiazolidinedione?
pioglitazone
2 main SEs of thiazolidinediones
- weight gain
- fluid retention
-gliptins vs -gliflozins vs -tides
- gliptins = DPP-4 inhibitors
- gliflozins = SLGT2 inhibitors
- tides = GLP-1 agonists
what do DPP-4 inhibitors do?
increases incretin levels which inhibit glucagon secretion
DPP-4 inhibitors are generally well tolerated but what is there a risk of?
pancreatitis
SGLT2-inhibitors MoA
inhibit reabsorption of glucose on the kidney
GLP-1 agonists MoA
Incretin mimetic which inhibits glucagon secretion
GLP-1 agonists SEs
- nausea and vomiting
- pancreatitis
what do SGLT-2 inhibitors and GLP-1 agonists typically result in?
weight loss
what is ketosis and when can it occur?
- build up of ketone bodies in the blood
- can arise through a range of circumstances, inc diabetic ketoacidosis (DKA), alcoholic ketoacidosis and starvation
DKA occurs primarily in which type of diabetes?
1
due to the lack of insulin in t1d, glucose cannot enter cells and so cannot be used for _______ or ________
glycogensis or glycolysis
glucagon levels in diabetes ?
high
in diabetes FAs are needed for energy production and thus beta-oxidation is stimulated by hormones such as what?
glucagon, adrenaline and cortisol
the large turnover of FAs in diabetes yields large amounts of what? what happens to it in excess?
acetyl-CoA — in excess is converted to ketones, leading to ketosis
what results are needed to diagnose diabetic ketoacidosis?
- glucose >11mmol/L
- serum ketones >3mmol/L
- ph <7.3
acetone often smelt on breath as acetoacetic acid is converted to acetone
