diabetes Flashcards
type 2 Diabetes Mellitus: define type 2 diabetes mellitus, recall the epidemiology, explain the aetiology, pathophysiology, clinical presentations and explain the physiological basis of treatment
define DM
state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues (notably retina, kidney, nerves and arteries)
T2DM: ketosis
not ketosis prone, but occasionally occurs
what 3 modifiable things does T2DM often involve
weight, lipids, BP
normal, impaired fasting glucose and diabetes levels when fasting
normal: <6mmol/l; impaired glucose fasting: 6-7mmol/l; diabetes: >7mmol/l
normal, impaired glucose tolerance and diabetes levels when 2 hours after fasting glucose tolerance test
normal: <7.8mmol/l; impaired glucose tolerance: 7.8-11.1mmol/l; diabetes: >11.1mmol/l
random diabetes level
> 11.1mmol/l
what is there a risk of at impaired fasting glucose levels (6-7mmol/l)
developing macrovascular disease (atheroma in cerebral circulation and heart etc.), after microvascular disease (retinopathy etc.)
epidemiology of T2DM
most prevalent DM and increasing, associated with increased aged (but now in children due to obesity - genetic condition accelerated by certain lifestyles), greatest in ethnic groups that move from rural to urban
inheritance of T2DM
autosomal dominnat condition, but unknown gene location
what is important for T2DM development
genes, intrauterine environment, adult environment
mechanism of T2DM pathophysiology
insulin resistance (less effective) and lack of insulin due to insulin secretion defects (not absolute, as enough insulin to switch off ketone production, but not enough to switch off hepatic glucose output)
why are fatty acids important in pathogenesis and complications of T2DM
some can damage B-cells, and are important in insulin resistance
what is MODY and how is it useful in T2DM pathophysiology
maturity onset diabetes of the young, which is relatively uncommon but gives useful metabolic insights into T2DM as has known genes
hereditary forms and inheritance of MODY
1-8 ineritance forms, and is autosomal dominant so positive family history
pathophysiology of MODY
ineffective B-cell insulin production and glucose sensation, latter caused by mutation of transcription factor genes and glucokinase gene
presentation of weight with MODY
no obesity, unlike most T2DM
how do genes operate through insulin resistance
operate through local factors from adipocytokines, wearing down susceptible B-cells by producing more insulin throughout whole life
effect on intra-uterine growth restriction (IUGR) on foetus and genes
lack of calories in utero can modulate gene expression throughout life (light babies at 1 year more likely to have diabetes or impaired glucose tolerance)
what progresses insulin resistance in adulthood
obesity and certain fatty acids
impact of metabolic dyslipidia in insulin resistance
causes atheroma progression and macrovascular disease (build up of fat in coronary and cerebral circulation for years before high sugar detected); also caused by mitogenic induction and inflammation
how is B-cell failure brought about following insulin resistance and outcome on metabolic defects and microvasculature
genetic predisposition so can’t make enough insulin, causing metabolic defect and dyslipidaemia to become worse, as well as hyperglycaemia causing microvascular disease
requirement of B-cell failure following insulin resistance
B-cell failure can go on to become absolute, so whilst initial treatment of diet, may eventually need insulin (haven’t changed diagnosis -> insulin deficiency more absolute)
insulin resistance and postential insulin secretion graph: description of both as age increases in normal and T2DM individuals
as get older, insulin resistance (intra-uterine environment) and secretion (genes) increases (unsure in childhood; increases due to microbiota and adipocytes); in those with T2DM, insulin secretion decreases (pancreas makes more immature insulin which doesn’t work properly), so at some point, insulin resistance will be in excess of insulin secretion (even with exercise, diet and medication), so won’t be able to make enough to overcome resistance (absolute insulin deficiency)
describe heterogenous presentation of T2DM
variable as BP, cholesterol, glucose etc. may all be more significant in individuals; some more about resistance than secretion deficit and vice versa
effects of dyslipidaemia in T2DM on vasculature
more cholesterol carried as LDL, damaging arteries, which if found too late presents with heart attack, blindness etc. (acute and chronic)
normal pathway of triglyceride breakdown products and metabolism; normal pathway of glycogen in liver; effects on heaptic glucose output
glycerol and NEFA taken to liver by omental circulation; NEFA can’t be used to make glucose (makes VLDL, which then makes triglycerides in adipocytes), but glycerol can be in liver (gluconeogenesis), as can glycogen (glycogenolysis) -> increased hepatic glucose output
effect of insulin resistance on glucose uptake and storage and hepatic glucose output, and lipolysis
less glucose uptaken into muscles and liver, so less stored as glycogen, with hepatic glucose output continuing unabated; excess lipolysis increases atherogenic lipid profile
normal, developing diabetes and T2DM response to glucose tolerance test
glucose clamped at high levels; in normal individuals, there is a large release of insulin (1st phase), before more is made and released (2nd phase); in developing diabetes, insulin secretion fails, so less able to make 1st phase insulin and more over next 2 hours; there is chronically insufficient insulin in diabetes
what is a major endocrine organ involved in T2DM, and how is it predictive of diabetes
adipocytes as make whole range of hormones; all hormones are important in diabetes mechanism (not cause) as a means by which changed metabolism comes about; adiponectin deficiency is associated with decreased insulin resistance
type of obesity in T2DM
central adiposity more important than omental adiposity as more metabolically active and endocrine important, as drain directly to liver
relationship and effect of obesity and gut microbiota
microbiota can change in obesity and enter liver, altering metabolism including inflammation and host signalling
weight gain as a side effect of diabetes treatment, and significance of metformin
metformin is only drug that doesn’t cause weight gain so first line treatment for T2DM-associated weight gain; all others including insulin cause weight gain (less urination etc.)
presentation of T2DM
osmotic symptoms, infections (high sugar), obesity, acute complications (hyperosmolar coma), chronic complications (ischaemic heart disease, retinopathy etc,)
4 categories of complications of T2DM and its treatment
microvascular, macrovascular, metabolic, treatment (hypoglycaemia)
3 microvascular complications of T2DM
retinopathy, nephropathy, neuropathy
4 macrovascular complications of T2DM
ischaemic heart disease, cerebrovascular, renal artery stenosis, peripheral vascular disease
2 metabolic complications of T2DM
lactic acidosis (less common than ketoacidosis in T1DM), hyperosmolar
4 basis of management of T2DM
education, diet, pharmacological treatment, complication screening
3 reasons to treat those with T2DM
reduce symptoms, reduce chance of acute metabolic complications (unlikely in T2DM), reduce chance of long term complications
7 things to eat and why in controlling T2DM
control total calories/increase exercise (weight), reduce refined carbohydrate (less sugar), increase complex carbohydrate, reduce fat as proportion of calories (less insulin resistance), increase unsaturated fat as proportion of fat (ischaemic heart disease), increase soluble fibre (longer to absorb carbohydrates), address salt (BP risk)
4 things to monitor in T2DM
weight, glycaemia, blood pressure, dyslipidaemia
drug used to promote weight loss and how it works
orlistat, as GI lipase inhibitor
surgical intervention to increase weight loss
gastric bypass, improving diabetes control as hormones made by gut modulate energy intake (food contact with duodenum important in satiety control)
when is metoformin administered and what does it do
administered in overweight patients with T2DM where diet alone has not succeded; reduces insulin resistance and hepatic glucose output, and increases peripheral glucose disposal
side effects of metformin
GI, and not used if severe liver or cardiac failure, or mild renal failure
what is fiver to reduce hepatic glucose output if B-cells are destroyed in T2DM
insulin
what do sulfonylureas and meglitinides do in treatment of T2DM, and how; side effect and therefore patients treated
stimulate B-cells to make and secrete more insulin when glucose response in B-cells not working but other machinery is, by shutting ATP-sensitive K+ channel, therefore causing Ca2+ channels to open and insulin to be released; does cause weight gain (only effective in lean with not enough insulin)
what does acarbose (a-glucodisade inhibitor) do in treatment of T2DM; side effect
slow down glucose absorption in gut and prolongs absorption of oligosacchardies, allowing insulin secretion to cope following 1st phase insulin; side effect flatus due to small bowel microbiota
what do thiazolidinediones (peroxisome proliferator-activated receptor agonists e.g. pioglitazone) do in treatment of T2DM; side effects
distributes weight from dangerous central to peripheral as peripheral insulin sensitiser; also improves lipids and sugar; side effects of older types hepatitis, heart failure
what do GLP-1/DPP4 inhibitors do in treatment of T2DM
benefit endogenous B-cells, with anti-glucagon effect
describe the incretin effect
oral glucose stimulates greater insulin production than IV glucose due to incretins (gut peptides)
what is glucagon like peptide-1 (GLP-1) secreted in response to, what is it a product of and its source, and what does it do
secreted in response to nutrients in gut; transcription product of proglucagon gene, mostly from L cells; stimulates insulin, suppresses glucagon
what does GLP-1 do and what is it effective in treating/promoting
increases satiety, restores B-cell glucose sensitivity and is effective for sugar and weight loss
GLP-1 degradation: time, enzyme and therapeutic option
short half life (rapid degradation) by dipeptidyl peptidase-4 (inhibited by DPPG-4 inhibitor)
2 examples of GLP-1 agonists
exenatide, liraglutide
administration of GLP-1 agonists
injection
what do long acting GLP-1 agonists do
decrease [glucagon] and [glucose], causing weight loss
other name for DPPG-4 inhibitors
gliptins
what do DPPG-4 inhibitors do
increase half life of exogenous GLP-1, increase [GLP-1], decrease [glucagon] and [glucose], but neutral effect on weight loss
what do SGLT2 inhibitors do
in treatment of T2DM
act on proximal tubules of neprhon, so increase glycosuria to remove glucose
example of SGLT2 inhibitor
empaglifozin
mechanism of empaglifozin action
inhibits Na-Glu transporter, increasing glycosuria, lowering HbA1c and reducing heart failure risk (Na+ transport in heart)
2 other aspects of control of T2DM
blood pressure, diabetic dyslipidaemia
what is gestational diabetes
temporary diabetes when pregnant
screening for diabetes: 3 problems of diabetes
mortality, morbidity, cost
screening for diabetes: difficulties in screening
specific unclear (which test, how often, who etc.)
screening for diabetes: difficulties in making a diagnosis
which glucose level is taken (fasted or stimulated), what determines high risk etc.
why is DM worth screening for
T2DM onset is preventable, with lifestyle intervention the most effective option at preventing progression vs metformin etc.
T1DM vs T2DM: prevalence
T1DM much less than T2DM
T1DM vs T2DM: typical age
T1DM: child, adolescent; T2DM: middle-age +
T1DM vs T2DM: onset
T1DM: acute; T2DM: gradual
T1DM vs T2DM: habitus
T1DM: lean; T2DM: often obese
T1DM vs T2DM: family history
T1DM: uncommon; T2DM: common
T1DM vs T2DM: geography
T1DM: europids; T2DM: less europids
T1DM vs T2DM: weight loss
T1DM: usual; T2DM: uncommon
T1DM vs T2DM: ketosis prone
T1DM: yes; T2DM: no
T1DM vs T2DM: serum insulin
T1DM: low/absent; T2DM: variable
T1DM vs T2DM: HLA association
T1DM: DR3, DR4; T2DM: none
T1DM vs T2DM: islet B cells
T1DM: destroyed; T2DM: function
T1DM vs T2DM: islet cells autoantibodies
T1DM: present; T2DM: absent
