16. Type II diabetes mellitus Flashcards
What happens to ketones in the body in T2D?
- Abnormal ketones in blood or urine if glucose is high
* Ketosis not seen
What are the values for fasting glucose, 2 hour glucose and glucose at any time in diabetes mellitus?
- Fasting glucose > 7 mmol/l
- 2 hour glucose > 11 mmol/l
- Any time > 11 mmol/l
What does a fasting glucose level between 6 and 7, and a 2 hour glucose between 7.8 and 11.1 show?
- Impaired fasting glucose (fasting glucose)
- Impaired glucose tolerance (2 hour glucose)
- Increased macrovascular risk
- Diabetes risk
- Not a microvascular risk (only with diabetes)
Describe the pathophysiology of T2D
- Genetic condition - genes, intrauterine environment and adult environment have a role
- Practically all patients are insulin resistant
- Patients also have an insulin secretion defect
- Fatty acids are important in the pathogenesis and lead to complications
What is maturity onset diabetes of the young (MODY)?
- Genetic disease (autosomal dominant) - all patients have a positive family history, and no obesity
- Several hereditary forms (8)
- Ineffective pancreatic insulin production
- Mutations have been found in transcription factor genes for insulin, and the glucokinase gene
- Specific treatments for the different types
When does T2D start to affect a patient?
• Defective genes contribute to insulin resistance throughout an adult’s life (and probably childhood)
• Patient already need more insulin, 30 years before being hyperglycaemic
- mechanisms brought about by adipocytokines (hormones made by fat cells)
- these hormones are a mechanism of the diabetes
What are the genes for T2D associated with?
• Being born light (epigenetic effect is not known)
• Obesity and handling of fatty acids
- obesity is not just a precipitant of diabetes, but part of the mechanism
What is dyslipidaemia and what does it involve?
- Abnormal amount of lipids in the blood
- Involves abnormal handling of cholesterol
- Along with the other effects of insulin resistance (mitogenic), this leads to macrovascular disease
Are identical or non-identical twins more likely to suffer from diabetes?
Identical twins
As people become older, they become more insulin resistant, so why do most normal people not have problems with hepatic glucose output and muscle glucose uptake?
- Able to produce more insulin to overcome this
* Individuals with diabetes can’t do this, as they become insulin deficient
What are products from the breakdown of triglycerides in adipocytes used for?
- Triglycerides break down to release glycerol and non-esterified fatty acids
- Fatty-acids contribute to the very low density lipoprotein triglyceride production
- Glycerol contributes to glucose production (but this glucose is unfortunately not taken up in diabetes along with unsuppressed HGO)
What percentage of T2D patients are obese at presentation?
80%
What are perturbations in gut microbiota associated with (with reference to diabetes)?
- Obesity and insulin resistant T2D
- Host signalling
- Fermentation of bacterial lipopolysaccharides to short chain FA
- Bacterial modulation of bile acids
- Inflammation, signalling metabolic pathways
(most studies are correlative but the mechanisms aren’t confirmed)
Why could the intra-uterine environment be significant in diabetes?
- Involved in programming insulin resistance for line
- So far, genes associated with diabetes are involved with insulin secretion
- Microbiota also comes from out mother, which may alter and express defects
What are the T2D presentations?
• Osmotic symptoms
- decreased glucose reabsorption
- glucose leaks out of the urine, taking water with it (polyuria, polydipsia)
• Infections
- yeast and microorganisms thrive in high glucose environments
• Acute: hyperosmolar coma
• Chronic: ischaemic heart disease, retinopathy
What are the complications of T2D?
- Microvascular - retinopathy, nephropathy, neuropathy
- Macrovascular - ischaemic heart disease, cerebrovascular disease, renal artery stenosis, PVD
- Metabolic - lactic acidosis, hyperosmolar complications
What medication can be used to treat T2D?
• Weight - orlistat (GI lipase inhibitor)
• Glycaemia
- metformin and insulin
- sulphonylureas and metaglinides
- alpha-glucosidase inhibitors
- thiazolidinediones (act on central adiposity)
- GLP-1, and DPP4 inhibitors (prolong GLP-1 action) - newer agents
- SGLT2 inhibitors - increases glycosuria
• Blood pressure treatment
• Dyslipidaemia treatment
What invasive procedure can be used in the treatment of T2D?
- Gastric bypass
* However trials showed that adverse effects and nutritional deficiency increased
What is metformin and how does it work?
- Biguanide, acts as an insulin sensitiser
- Given to overweight patients with T2D, where diet alone has not succeeded
- Reduces insulin resistance - reduces HGO and increases peripheral glucose disposal
- GI side effects, but it is very safe and effective
- Do not use if suffering from severe liver, severe cardiac or mild renal failure
What is a sulphonylurea and how does it work?
- Glibenclamide, an insulin secretagogue
- Given to lean patients with T2D
• When glucose enters the cell:
- it is metabolised with glucokinase acting as a glucose sensor
- ATP-sensitive K channel are blocked
- Ca2+ influx inducing insulin vesicle movement + release
• Sulphonylureas can bypass this and block the channel
• This induces insulin release
• Side effects - hypoglycaemia and weight gain
What is acarbose and how does it work?
- Alpha glucosidase inhibitor
- Acts within the gut to prolong glucose and oligosaccharide absorption
- Allows insulin secretion to cope, following defective first phase insulin
- As effective as metformin
- Side effects - flatus (gas)
What is the incretin effect?
Food stimulates more insulin secretion if given orally rather than IV
What does GLP-1 do?
- Secreted in response to nutrients in the gut
- Stimulates insulin and suppresses glucagon
- Decreases [glucose]
- Transcription product of the pro-glucagon gene, mostly from L cells
- Increases satiety
- Restores B cell glucose sensitivity
- Short half-life, rapid degradation from enzyme dipeptidyl peptidase-4
How can we manipulate the effects of GLP-1 clinically?
• GLP-1 agonists: exenatide, liraglutide - injectable, long acting GLP-1 agonist • Gliptins: DPPG-4 inhibitors - oral agents - increases half-life of GLP-1, increasing [GLP-1]
