Diabetes Flashcards
What is diabetes mellitus?
genetic predisposition and an autoimmune process causing gradual destruction of the beta cells of the pancreas, leading to no insulin production
deficiency or deminished effectiveness of endogenous insulin, hyperglycemic, deranged metabolism and causing microvascular problems
What are the different types of DM?
type 1 - failure to produce sufficient insulin
type 2 - the body’s resistance to insulin
gestational - high blood glucose levels during pregnancy, causing risk to mother and foetus
maturity onset diabetes of the young - monogenetic defects of B cell function (impaired insulin secretion), appearing as mild hyperglycaemia at a young age, autosomal dominant
secondary - from pancreatic disease,cystic fibrosis, cushing’s, acromegaly, thiazide diuretics, corticosteroids, congenital lipodystrophy, acanthosis nigricans, wolframs syndrome
What is the pre diabetic phase?
where auto immunity has been developed but no clinically apparent insulin dependency, insulin autoantibodies can be developed in genetically predisposed
triggered by viruses, dietary factors, enviromental toxins, emotional or physical stress, early cessation of breast feeding
Risk factors for type 1 diabetes?
10% have family history, associated with HLA DR3 and DR4 and islet cell antibodies, Caucasian, North Europe, Scandinavian, 30-50% concordance in twins, associated with other auto immune disease, eventual dissapearnace of C peptide, 6q determines islet sensitivity to damage
At what age does type 1 DM usually present itself?
juvenile onset, but can occur at any age
When does type 2 DM usually occur?
over 30, but becoming increasingly common in children and adolescents, polygenic disorder
Risk factors for type 2 DM?
excess body weight, physical inactivity, alcohol, south asia, history of gestational diabetes, impaired glucose tolerance, impaired fasting glucose, drug therapy, low fibre, hyglycaemic index diet, metabolic syndrome, polycystic ovarian syndrome, family history, male, elderly
Pathophysiology of type 2 DM?
the genetic form has mutations of the insulin receptor and structural alterations of the insulin molecule so patients gradually become insulin resistant and beta cells fail to secrete enough insulin and beta cell mass is reduced to 50% of normal, the C peptide persists
How do all DM present?
polyuria, polydipsia, lethargy, boils, glycosuria, blurred vision, thirst, signs of micro and macrovascular disease, pruritus, frequent and recurrent infections
Symptoms only in type 1 DM?
weight loss, dehydration, ketonuria, acetone breath, Kussmaul breathing, nausea, vomiting, hyperventilation, acute with short duration of symptoms
Symptoms only in type 2 DM?
acute and chronic complications, subacute with a longer duration of symptoms
Diagnosis of DM?
2 fasting venous plasma glucose - >7mmol/L
random plasma glucose and symptoms >11.1mmol/L
HbA1c >6.5% (48mmol/mol)
Fasting plasma glucose 11.1mmol/L
impaired fasting glucose 5.6-6.9mmol/L
Management of DM?
educate, self management, healthy diet, weight loss, smoking cessation, regular exercise, low sugar, high starch, glucose control, glucose and HbA1c monitoring, early detection, monitor complications, global assessment of cardiovascular risk, antidiabetic agents
Treatment of type 2 diabetes?
oral hypoglycemic agents, along with diet and lifestyle changes to get good glyaemic control
Function of insulin?
regulated carb and fat metabolism affecting the liver, muscle and fat tissue, causing glucose uptake
inhibits the release of glucagon and blocks fat being used as an energy source
stores excess energy
promotes the uptake of glucose from the blood into the liver and the conversion of glucose into glycogen and glucose to acetyl coA to triglyceroles into VLDL to be stored triglycerol in adipose tissue
Where is insulin synthesized?
in the pancreas, in the beta cells of the islets of Langerhan
What is insulin synthesized from and how?
synthesized from the preproinsulin, moves into the endoplasmic reticulum and then converted into proinsulin precursor by proteolytic enzymes known as prohormone convertases and exoprotease carboxypeptite E
splits the proinsulin precursor into A, B and C, A and B are joined by diastole bonds to make insulin and the C peptide helps G protein membrane
When is insulin released?
in response to increased blood glucose levels and then it is sustained with the slow release of newly formed vesicles, triggered independently of sugar
What stimulates insulin release?
GLUT 2 carries glucose into the beta cells, stimulating insulin release
How does insulin affect amino acids?
uptake of amino acids from the blood stream to the liver
then causes proteinogenesis and protein synthesis
How does insulin affect fat?
promotes storage of fat in skeletal muscle as fatty acids
synthesis of triglycerol
stores excess energy
What is the insulin receptor?
a tyroxin kinase receptor made up of 2 beta, 2 alpha and 2 tyroxin kinase (an enzyme which is usually inactive) subunits
When does tyroxin kinas become active?
when it has a phosphate group coming off it
insulin binds to the alpha subunits of the insulin receptor, causing the tyroxin kinase to become phosphorylated to be activated
What happens when the insulin receptor (tyroxin kinase) is activated?
intracellular effects of insulin occur from IRS-1 stimulation
promotes growth, gene expression, glycogen synthesis, fat synthesis, protein synthesis, increased glucose transporter expression (GLUT2 in liver and GLUT4 in muscle), so there is an uptake of glucose into the liver
What causes insulin resistance?
insulin cannot bind to tyroxin kinase receptor so there is not an increase of GLUT2 receptors so glucose remains in the blood steam
What happens to glucose in the liver?
stored as glycogen or converted to fats and turned into VLDLs and transported into adipose tissue
How does insulin affect blood glucose levels?
decreases them
What effect does insulin have on enzymes?
inhibits glycogen phosphorylase into glucose and then promotes hexokinase and glycogen synthase to form glycogen, increased glucose transporters to liver and muscle, stimulate ribosome activity to make proteins and inhibits protein degradation and increase glycolysis for fat synthesis, and prevents beta oxidation
After lifestyle changes, what is the first medication used for type 2 diabetes treatment and how does it work?
Biguanides e.g. metformin - phosphorylates GLUT4 to increase glucose transport uptake and reduces glucose production from the liver, sensitizing target tissues to insulin
Why is metformin more effective in type 2 diabetes, and only used in type 1 if overweight?
it can only act in the presence of endogenous insulin so needs residual functioning pancreatic islet cells
Benefits of metformin?
reduces macrovascular complications and death, fewer hypoglycaemic attacks then sulphonylureas, does not cause weight gain, can be used in combination
Risk of metformin?
can cause lactic acidosis, has GI side effects at higher doses (nausea, vomiting, anorexia), an insulin secretagogues and has drug interactions with ACE-I, alcohol, NSAIDs, steroids and contrast agents
Who is most at risk of lactic acidosis in metformin use?
renal insufficiency, CV disease, PVD, liver disease, pulmonary disease, >65
What is the second line medication that can be used for type 2 diabetes treatment and how do they work?
Sulphonylureas e.g. glipizideare - block potassium channels on cell membrane, increasing pancreatic islet cell function
opens calcium channels, increasing fusion of insulin granulae with the cell membrane to increase insulin release
stimulates glycolytic pathway in the liver and inhibits glucose production
Benefits of sulphonylureas?
last 12-24hrs, good if metformin is CI, reduced glycosylated Hb (HbA1c) over a ten year period
Risks of sulphonylureas?
hypoglycaemia, weight gain, liver dysfunction, GI disturbance, CI in renal failure, hepatic failure, porphyria, pregnancy, breast feeding, drug interactions with ACE-I, alcohol, NSAIDs and steroids
In who is hypoglycaemia from sulphonylureas most common?
older age, mild-moderate hepatic impairment, renal impairment
How can hypoglycaemia be reduced in sulphonylurea use?
use a short acting drug like tolbutamide
How do rapid acting insulin secretagogues treat type 2 DM?
they are post prandial glucose regulators e.g. repaglinide and nateglinide - block potassium channels on pancreatic beta cells, stimulating insulin release, short acting
Benefits of rapid acting insulin secretagogues?
short duration and rapid onset
repaglinide is better for irregular meal times and for poor glycaemic control and target post prandial hyperglycaemia
nateglinide is used with metformin and is a sulfonylurea receptor binder given before meals
Risks of rapid acting insulin secretagogues?
hypoglycaemia, weight gain, CI in hepatic failure, pregnancy and weight gain, drug interactions with ciclosporin, trimethoprim and clarithromycin
What is the third medication given in type 2 DM treatment and how does it work?
Thiazolidinediones (TDZs)/glitazones e.g. pioglitazone - activates nuclear peroxisome proliferation activated receptor (PPAR) which regulates genes that influence insulin sensitive genes to enhance production of mRNAs of insulin dependent enzymes and increasing hepatic sensitivity to insulin, enhancing glucose clearance
Benefits of TDZs?
used in combination with S or M, TDZ with M is good for obese patients but can cause deterioration of blood glucose control
pioglitazone can be used with insulin therapy if this happens
Risks of TDZs?
weight gain, hypoglycaemia, hepatoxicity, fracture risk, CI in heart failure due to fluid retention and cardiac failure risk, hepatic disease and type 1 DM, drug interactions with rifampicin and paclitaxel
How does Acarbose treat type 2 DM?
inhibits intestinal alpha glucosidases to delay absorptions and digestion or sucrose and starch and slows glucose absorption, reduces post prandial peaks
Benefits of acarbose?
use if all other CI, improves glycaemic control, can be used in combination
Risks of acarbose?
Gi disturbance, flatulance, bloating, CI in thyroid cancer, MEN2, drug interactions with orlistat and pancreatin
What is orlistat and how does it work?
an intestinal lipase inhibitor which reduces fat absorption for weight loss
What are incretins?
they increase insulin release from beta cells post eating before glucose levels become elevated
2 types: glucagon like peptide 1 (GLP1) and gastric inhibitory peptide (GIP)
What inactivates incretins?
dipeptydyl peptidase 4 (DPP4)
Why is GLP1 not as useful in diabetic treatment and what could be used instead?
has a very short half life and must be given as a continuous SC injection
treatment to inhibit DPP4 which inactivates GLP1 would be more successful e.g. sitagliptin and vildagliptin
Benefits of DDP4-I?
can be used in combination if good glycaemic control, and good for those at risk of hypoglycaemia
