Diabetes Flashcards
Describe the Regulation of CHO metabolism in non diabetic humans: Fasted
- all glucose comes from liver (and a bit from kidney)
* Breakdown of glycogen
* Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol) - Glucose is delivered to insulin independent tissues, brain and red blood cells
- Insulin levels are low
- Muscle uses FFA for fuel
- Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat
Describe the Regulation of CHO metabolism in non diabetic humans: Post feeding
- After feeding (post prandial) - physiological need to dispose of a nutrient load
- Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
- 40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
- Ingested glucose helps to replenish glycogen stores both in liver and muscle
- High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall
what is the Site of insulin and glucagon secretion
pancreas - islets of langerhan
which cell secretes insulin
Beta cell in panceas
which cell secretes glucagon
Alpha cells - pancrease
what are the Key hormonal regulators of carbohydrate metabolism
Insulin
* supresses hepatic glucose output
1. reduces Glycogenolysis and Gluconeogenesis
* Increases glucose uptake into insulin sensitive tissues
* Suppresses lypolysis and breakdown of muscles
Glucagon (counter refulatory)
* Increases hepatic glucose output
1. increasing Glycogenolysis and Gluconeogenesis
* Reduce peripheral glucose uptake
* Stimulate peripheral release of gluconeogenic precursors (glycerol, AAs)
1. Lypolysis and Muscle glycogenolysis + breakdown
Others
* (adrenaline, cortisol, growth hormone have similar effects to glucagon and become relevant in certain disease states, including diabetes)
Describe Diabetes mellitus
- A disorder of carbohydrate metabolism characterised by hyperglycaemia
- Causes morbidity and mortality through
1. Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and
- hyperosmolar coma (Hyperosmolar Hyperglycaemic State )
Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular) - Side effects of treatment- hypoglycaemia
What are some Diabetes associated serious complications
Stroke
Diabetic neuropathy
Diabtetic nephropathy
CVD
Diabetic retinopathy
What are the types of diabetes
- Type 1
- Type 2 (inc gestational + caused by meds)
- Maturity onset diabetes of youth (MODY)
- Pancreatic diabetes
- “Endocrine Diabetes” (Acromegaly/Cushings)
What is the Pathogenesis of Type 1 diabetes
- insulin deficiency disease characterised by loss of beta cells (insulin producing) due to autoimmune destruction
- Beta cells express antigens of HLA histocompatability system perhaps in response to an environmental event (?virus)
- Activates a chronic cell mediated immune process leading to chronic ‘insulitis’
Describe Glucose metabolism and Type 1 diabetes
**Failure of insulin secretion leads to
**
* Continued breakdown of liver glycogen
* Unrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors
* Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
**Rising glucose conc causes increased urinary glucose losses as renal threshold (10mM) is exceeded
**
**Failure to treat with insulin leads to
**
* Increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose
* perceived ‘stress’ causes increased cortisol and adrenaline
progressive catabolic state and increasing levels of keto
Describe Glucose metabolism and Type 2 diabetes
**A consequence of insulin resistance and progressive failure of insulin secretion (but insulin levels are always detectable)
**
**Impaired insulin action leads to
**
* Reduced muscle and fat uptake after eating
* Failure to suppress lipolysis and high circulating FFAs
* Abnormally high glucose output after a meal
** low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive
**
what to Sulphonylureas (gliclazide, glibenclamide) do
- stimulate insulin release by binding to beta-cell receptors
- Improve glycaemic control (1-2% in HbA1c) at the expense of significant weight gain
- Do not prevent the gradual failure of insulin secretion
- Can cause hypoglycaemia (occasionally prolonged and fatal, particularly in the elderly and when renal function is impaired)
What do Thiazolidinediones (pioglitazone - ACTOS) do
- Bind to the nuclear receptor PPAR λ (peroxisome proliferator-activated receptor)
- Activate genes concerned with glucose uptake and utilisation and lipid metabolism
- Improve insulin sensitivity
*
What would An ideal drug in Type 2 diabetes do
- Reduce appetite and induce weight loss
- Preserve b-cells and insulin secretion
- Increase insulin secretion at meal time
- Inhibit counterregulatory hormones which increase blood glucose such as glucagon
- Not increase the risk of hypoglycaemia during treatment
what are Effects of GLP-1
- GLP-1 is secreted by L cells in intestine
- Stimulated insulin secretion
- suppresses glucagon
- slows gastric emptying
- reduces food intake
- increases b-cell mass and function
- improves inculin sensitivity
- enhances insulin disposal
Native GLP-1 is rapidly degraded by what
DPP-IV
list Oral agents to treat diabetes
- Metformin first line
- Sulphonylureas are no longer the second line agents of choice
- DPP-IV inhibitors, GLP1 analogues, SGLT-2 inhibitors are replacing sulphonylureas
- Use of glitazones rarely used
Why does obesity cause Type 2 diabetes?
Obesity (particularly central) impairs insulin action. In those, already insulin resistant due to genetic factors and who have progressive impairment in insulin secretion this brings out diabetes at an early stage.
Why doesn’t DKA (diabetic ketoacidosis) occur in Type 2 diabetes?
It is rare because the low insulin levels are sufficient to suppress catabolism and prevent ketogenesis. It can occur if hormones such as adrenaline rise to high levels (eg during an MI)
Why does insulin secretion become impaired in Type 2 diabetes?
- Main factor is lipid deposition in the pancreatic islets which prevent normal section of insulin
- genetic predisposition (i.e. abnormalities of insulin secretion in first degree relatives)
- ‘glucotoxicity’ hyperglycaemia inhibits insulin secretion
what are 3 different insuling treatment approaches for diabetes
- once daily basal - type 2 only
- Twice daily mix insulin - Both
- Basal bolus thereaby- mostly 1, sometimes 2
List the advantages and disadvantages for basal insulin used in type 2 diabetes
Advantages
* simple to use - based of fasting measurments
* less risk for night hypoglycemia
* pairs with oral therapy
Disadvantages
* Doesn’t cover meals
* best paired with long acting insulin anoglogues which are expensive
Liat the advantages and disadvantages of pre mixed insulin used for diabetes
Advantages
* can cover insulin requirments most of day
* both basal and prandial in a single insulin prep
Disadvantages
* not physiological
* constant meal and exercise pattern
* cannot separately titrate individual insulin components
* risk nigh hypoglycemia
* risk of fasting hyperglycermia if badal component doesn’t last long enough
* often requires high Hbac1 goal of 7.5-8%>
List the current classification of hypoglycemia in diabetics
Level 1 Alert - below 3.9 mmol/l - no symptoms
Level 2 - Serious biochemical - plasma glucose under 3mmol/l
Level 3 Severe - impaired cognitive function sufficient to require external intervention
what are the pathologvcal effects caused on organs by hypoglycemia
Brain
* Cog dysfunction
* black outs
* seizures
* coma
heart
* risk heart attack and arrthmia
Musculoskeletal
* falls
* fractures
* dislocations
Circulation
* inflammation
* coagulation abnormalities
* endothelial dysfunciotn
* haemodynamis changes
what are some autonomic symptoms of hypoglycemia
- Trembling
- palpitation
- hunger
- sweating
- anxiety
What are some neuroglycopenic symptoms of hypoglycemia
- difficulty concentrating
- confusion
- weakness
- vision changes
- drowsiness/dizziness
- difficulty speakig
what are some strategies to combat hypoglycemia: Patient education
- discuss risks of hypoglycemia and treatment with insulin/sulphonylureas
- educate patients and care givers how to recognize hypoglycemia
- instruc patients to report incidents of hypoglycemia to doctor
*
How do you treat hypoglycemia (RCTRE)
- Recognise symptoms
- Confirm need for treatments (below 3.9 mmol/l)
- Treat 15g fast acting carbohydrate tp relieve symptoms
- Retest 15 mins after to make sure blood glucode minimum 4 and retreat is not
- Eat long acting carbohydrate tp prevent future incidents
