Lec 45- Diabetes 1 Flashcards
Diabetes mellitus and its treatment
-As background you should revise introductory material on endocrinology, glucose homeostasis and diabetes from earlier parts of the course Present lecture series
+Clinical features of type 1 and type 2 diabetes
+Complications of diabetes
+Principles of treatment
+Glucose-lowering drug therapies
+insulins
Quick reminder: insulin is the main hormone controlling glucose homeostasis
- Pancreas (Beta cells from the islets of Langerhans) -> produces insulin
- Insulin reduces output of glucose from liver
+It encourages uptake of glucose into muscle
NB- Alpha cells of islets of Langerhans produce glucagon
Vital importance of glucose homeostasis (and if glucose gets to low)
-Glucose is the vital source of energy for the brain (5g of glucose per hour)
+The main rapid source of energy for most tissues
-IF glucose gets TOO LOW
+This can deprive the brain of energy
+Neuroglycopenia impairs neural function and can result in coma and death
+Low glucose activates multiple ‘Counter-regulatory’ mechanism
e.g. stimulates the SNS and various hormones (Glucagon, adrenalin, glucocorticoids, growth hormones) that act to raise blood glucose
If glucose gets to high
- State of diabetes mellitus exists. Adversely alters nutrient metabolism
- Glycates proteins leading to microvascular disease (Retinopathy, nephropathy), neuropathies and increases risks for microvascular diseases
- Osmotic diuresis causes dehydration, hyperosmolar state can precipitate circulatory collapse
- Severe insulin deprivation causes fatal ketocidiotic come
Origins of ketoacidosis
- Severe insulin deprivation causes ketoacidosis coma
- Insulin will affect the metabolism of glucose and stop the metabolism fo fats
- If there is to much fatty acid release they become converted to ketones (which are acidic)
Metabolic effects of insulin
1) Increase glucose uptake= Muscle, fat
2) Increase glycogen storage= muscle, liver
3) Increase glycolysis= muscle, liver and fat
4) Decrease gluconeogensis= liver
5) Increase lipogenesis- liver, fat
6) Decrease in lipolysis- fat
7) Increase amino acid uptake- muscle
8) increase protein synthesis= Muscle and liver
9) Decrease catabolism= muscle
Diabetes Mellitus
- Group of metabolic disorders characterised by inappropriate hyperglycaemia (chronic excess glucose in blood)
- TYPE 1: due to absolute lack of insulin, due to destruction of pancreatic beta cells
- Type 2: due to impaired action of insulin (insulin resistance) and impaired secretion of insulin by pancreatic beta cells
Features of type 1 and type 2 diabetes
1) OTHER NAMES Type 1 (insulin dependant diabetes mellitus); Type 2 (Non-insulin dependant diabetes mellitus)
2) AGE OF ONSET Type 1= <20yrs; Type 2= Mostly over 40
3) % OF ALL DIABETES Type 1=<5%; Type 2= >90%
4) HYPERGLYCAEMIA type 1= severe; Type 2= mild to moderate
5) PANCREATIC B-CELLS Type 1= all destroyed; Type 2= dysfunctional
6) INSULIN SECRETION Type 1= None; Type 2= variable
7) INSULIN RESISTANCE Type 1= No; Type 2= Yes
8) MICROVASCULAR DISEASE Type 1= Yes; Type 2= Yes
9) MACROVASCULAR DISEASE Type 1= modest; Type 2= Severe
10) INSULIN TREATMENT Type 1= Always; Type 2= sometimes
Other types of diabetes
- Gestational diabetes
- Specidic genetic defects (monogenic diabetes) -Endocrinopathies)
- Diseases of exocrine pancreas
- Diabetes induced by drugs, chemical, infections
Pathogensis of type 1 diabetes
- Genetic susceptibility plus environmental ‘insults’ autoimmune destruction of beta cells
- Most (but not all) cases of type 1 diabetes are due to autoimmune destruction of islet of beta cells
- A small minority of cases are due to toxic chemicals or severe disease of the exocrine pancreas which lead to destruction of ilet beta cells
- This can be cause by virus’s which specifically target Beta cells (cause our own immune system to destroy them)
Immuno-pathogensis of type 1 diabetes
-Genetic susceptibility
+Risk 15x greater if T1 DM sibling
+Concordance in identical twins
+Strong linkage with several immunity-related chromosome loci that code for MHC HLA genes e.g. DRB1’03.DQ2
-Environmental triggers
+Viruses e.g. Mumps, rubella, retrovirus
+chemicals e.g. alloxan, streptozotocin, nitroso compounds
+Possible dietary compounds -Immune system activation
+Expression of altered proteins by islets B cells that trigger immune self destruction of these cells
+e.g. Islet cell Abs (ICA), glutamic acid decarboxylase (GAD) Abs, insulin Abs, CD4+8 T cell mediated ‘Autoimmune B-cell destruction’
Development of type 2 diabetes
- As people become overweight and obese
- Insulin resistance gradually increases
- This causes the B cell to increase function
- As time progress B cell function has to greatly increase in order to maintain glucose levels due to increased insulin resistance
- B cells start to fail, insulin resistnace increases, basal and prandial hyperglycaemia
- When you become insulin resistance, you start to lose weight (fat stores used)
- Microvascular complications (retinal, nepho and auto immune nerve)
- Macrovascular complications (arteries and veins, heart, brain)
Diagnosis of diabetes
SIGNS AND SYMPTOMS
-Fatigue -Thrist -Polyuria -Visual disturbances -Recent weight loss
CLINICAL BIOCHEMISTRY
- Random plasma glucose (>11.1)
- Fasting plasma glucose (>7.0)
- 2 hour post-OGGT (oral glucose tolerance test) plasma glucose (>11.1)
- HbA1c >6.5% or >48 mmol/mol
Glycated Hb (HbA1c)
- Long term (about 6weks) indicator of glycemic control
- Valine on B chain have glucose attached
- RBC destroyed at ~120 days ( Inaccuracies in HbA1c
- sickle cell anaemia etc
- Fe deficiency
- Anaemia
75g oral glucose tolerance test
- Overnight fast and blood sample at time 0
- Drink 75g of glucose solution at time 0-5 mins
- Blood samples at intervals for unto 2 hours
- <7.8= normal
- 7.8= IGT (impaired glucose tolerance)
- 11.1= diabetes
Complications of diabetes (acute and chronic)
Acute
- Hyperglycaemic coma: Type 1= ketoacidotic; Type 2= hyperosmolar
- Hypoglycaemia (excess treatment)
Chronic
- Microvascular: Retinopathy, nephropathy, neuropathy
- Macrovascular: MI, stroke, Peripheral vascular dis
Causes and consequences of type 1 diabetes
-Genetic inherited factors and Autoimmune B cell destruction –> -B cells destroyed –> -Severe hyperglycaemia –> Can cause acute emergencies –> Hypersomolar coma treatment induced hypoglycaemia -Hyperglycaemia-> Microvascular disease- > Retinopathy, Nephropathy,
Glucotoxicity causes microvascular complications
Mechanism
- Excess glucose causes non-enzymatic glycation of proteins, particularly proteins in the basement membranes of cells in the retina and renal glomeruli, and in peripheral nerves
- Polyol pathway (aldose reductase)- when polyols are in the cell they drag in water, this reduce axon ability for conductance leading to neuropathy
- Hexsamine pathway (GFAT)
- Advanced glycation end products
- Reactive oxygen species
- Protein kinase C
CLINICAL Consequences -Retinopathy -Nephropathy -Neuropathy (diabetic foot)
Diabetes prevalence in UK adults
- Scotland= 271,312 = 5%
- N ireland= 84,836= 5.4%
- England= 2,913,538 = 6.2%
- Wales= 183,348= 6.8%
Burden of diabetes
Mortality
- Life expectancy= Decrease 5-10 years
- Fatal coronary heart disease = increase 2-4 times
- Fatal stroke= Increase 2-3x
Morbidity
- CHD= increase 2-3x
- Cerebrovascular disease= Increase by at least 2x
- Peripheral vascular disease= increase 2-3x
- Retinopathy= 80% of patients Registered blind= 1%
- Nephropathy= 5-30% of paitents
- Peripheral neuropathy= 60% of pateints
- HTN= 60% of paitnets
At risk of diabetes
- Overweight (BMI>25) or obese
- Other features of metabolic syndrome
- Family history of type 2 diabetes
- Gestational diabetes or pther previous hyperglycaemia
- Ethnically predisposed (asain, hispanic, afro caribbean)
- Lack of physical exercise
- Atherothrombotic
- Smoker
- Cushings
- Potentially diabeticgenic drugs
- Recurrent infections or pruritus
Prevalance of diabetes in england by ethnic origin
- This shows there is varying prevalence dependant on ethnicity
- E.g. south asain and black carribean are more likely to get it
Principles of diabetes management
- General aim to enhance quality of life by relief and prevention of symptoms
- Confirm diagnosis
- Design a personalised care plan
- Treat existing symptoms and complications
- Lifestyle advice on Diet, exercise, weight control, health education and give psychological support
- Optimize glycaemia control: Glucose loweing drugs including insulin
- Detect and treat other conditions
- Detect and treat other risk factors
- Patients empowerment through ongoing education
Principles of diabetes management
- Diagnosis
- Care plan
- Symptoms
- Diet
- Weight
- Glucose
- Co-morbidities
- CV risk
- Education
Routine care
- Advice- diet exercise, weight, smoking
- Blood pressure- monitor
- Cholesterol- dyslipidaemia
- Diabetes control- treat hyperglyceamia
- Eye exams
- Foot examination
- Guardian drugs- statin, Anti-HTN, aspirin, treat co-morbidities
Management of diabetes- pharmacist
- Lifestyle/healthy living- Diet, exercise, weight control, psychologist support
- Self monitoring blood glucose
- Clinical visits long term glycaemic control- HbA1c
- BP, blood lipids, other clinical parameters- monitor and treat as required
- Treat co-morbidities- multi pharmacy; potential interaction
- Most middle aged and elderly diabetes patients are recommended to take a statin and sometimes low-dose aspirin: many will require anti-HTN therapy, many will be overweight and recommended to follow a weight-reducing diet with exercise
- Ask about eyes and feet
Diet management of diabetes
RECOMMEND
- High in complex carbohydrate- firbre rich
- Low in simple sugars
- Low in fats (especially saturate fats)
- Low in ChE
- Low salt
- Total energy (calorie) content adjusted aiming to achieve and maintain normal body weight
Main blood glucose lowering agents UK
1) Biguanide- metformin- Counter insulin resistance and decrease hepatic glucose production
2) Sulfonylureas- Gliclazide- stimulate insulin secretion
3) Meglitinides- Repaglinitde- stimulate insulin secretion
4) Thiazolidinedione- piolitazone- increase insulin sensitivity; Decrease hepatic glucose production
5) SGLT2 inhibitor-Dapagliflozin- increase renal glucose elimination
6) DPP-4 inhibitors- Sitaglipton- inhibit degradation of incretin hormones e.g. GLP-1
7) a-Glucosidase inhibitor- Acarbose- slow digestion of carbohydrates
8) GLP-1 receptor agonist- Exenatide- Stimulate insulin secretion; supress glucagon; slow gastric empyting
9) Insulin- Aspart,Lispro- Replace insulin; decrease hepati glucose production
Managing glucose control in type 2 diabetes
Diagnosis –>
- Lifestyle (diet, exercise, weight control, health education) –>
- Oral agent monotherapy (Metformin- not appropriate or not tolerated consider DPP4 inhibitor, SGLT2 inhibitor, repaglinide)
- Combinaiton therapy (2 different class of agent) –>
- Triple therapy –>
- Insulin other agents –>
NB AIM IMPROVE GLYCAEMIC CONTROL
Antidiabetic (glucose lowering) targets
- Pancreas (sulfonyluras, meglitinides, GLP-1 receptors, DPP-4 inhibitors) –>
- Insulin (insulin injections) –>
- Liver (increase blood glucose, metformin, TZD) –>
- GI tract (increase blood glucose, acarbose) –>
- Muscles (TZD)
- Kidneys (SGLT2 inhibitors)
NICE guidline treatment algorithm
- HbA1c after lifestyle intervention –>
- METFORMIN (if not tolerated give DPP4i or SU) ->
- If HbA1c >7.5->
- Metformin + DDP4i or Pio or SU or SGLT2i
- If HbA1c >7.5 –>
- Triple therapy (Met+DPP4i+SU or Met+Pio+SU or Met+(Pio/SU)+SGLT2i) –>
- Insulin + metformin + Other –>
- Monitor for deterioration –>
- Increase insulin dose, intensify regimen over time –>
Metformin- mode of action- intestine
- High metformin exposure
- Decreased mitochondrial GPD and complex 1
- Decreased ATP; AMP ration, Increase AMPK and decreased mTORC
NB- lactate is produced which affects the liver
THIS CAUSES
- Increased anaerobic glucose metabolism
- Increased Glucose turnover
- Increase GLP-1
=Decrease in hyperglycaemia
Metformin- mode of action- Liver
- Medium metformin exposure
- Lesser decrease mitochondrial and AMPK effects and AMPK effects
- Insulin receptor decrease phosphatases and post recepotr ttargets
- Decrease glucoagon action
THIS CAUSES
- Decreased gluconeogensis
- Decrease glycogenolysis
Metformin- mode of action- muscle
- Lower metformin exposure
- Increase AMPK
- Increase oxidative pathways
THIS CAUSES
- Increase glucose uptake and oxidation
- Increase glycogenesis
Biguanide- Metformin- how it act, advantages and disadvantages
COUNTER INSULIN RESISTANCE
- Decrease hepatic glucose production
- Increase muscle glucose uptake
- Increase Splanchnic (internal organ escpecially in abs) glucose turnover
+Not cause weight gain
+Not cause hypos
+Antihyperinsulinaemic
+May improve lipid profile
+Improve various vascular parameters
NB BIG ADVANTAGE REDUCE CV RISK
HOWEVER
- GI intolerance
- Risk of lactic acidosis
- Hyoxaemic state
- Renal resitrictions
Sulfonylureas and meglitinides
- SUs: gliclizide
- Stimulate insulin secretion; NB SUs last longer than glinides (prandial)
- Weight gain
- Risk of hypoglycaemia (important why driving)
Thiazolidinediones- PPARy agonist
- Thiazolidinedione –>
- Adipose tissue (increase in fatty acid uptake; lipogensis; glucose uptake)
- Muscle (Increase glucose uptake)
- Liver (Decrease gluconeogenesis)
HOWEVER
- Weight gain
- Slow onset of action
- Not cause hypoglycaemia
- Check liver function
- CHeck NYHA risk
- FLuid retention, oedema
- Risk of fractures
- Risk of HF
Alpha-glucosidase inhibitors (acarbose)
- Competative inhibitor for sucrose for alpha glucosidase enzyme on enterocytes
- Slow rate of carbohydrate digestion- must consume diet rich in comlex carbohydrates
- Not cause weight gain
- Not cause hypoglycaemia
- May not decrease triglycerides
- GI disease and flatulence
Incretin based therapies
-DPP4 inhibitors and GLP-1 receptors
DPP4 INHIBITORS
- Sitagliptin
- Vildagilptin
GLP-1 receptor agonists
- Exenatide
- Lixisenatide
Incretin based therapies
- This works by potentiating the effects of increasing insulin and decreasing glucagon
- Decrease gastric empyting
- Increase satiety (makes you feel full)
- Decrease body weight
Dipeptidyl peptidase-4 inhibitor (DPP-4)
- Sitagliptin
- doesnt cause hypoglycaemia
- Potential CV benifites
- Weight neutral
- However pancreatitis
SGLT-2 inhibitors
- SGLT1 brings in glucose from gut –> blood
- SGLT2 reabsorbs glucose from kidneys (PCT)
- By adding the inhibition we urinate out lots of urine
- Weight loss
- Not cause Hypo
- Reduce BP
- CV benefits
- Potential renal benefits
- Genital mycotic infections
- DKA if insulin reduced to much
GLP-1 receptor agonists
-Exenatide
Enhance incretin effect
- Increase glucose insulin secretion
- Decrease glucagon secretion
- Delay gastric emptying
Weight loss
Not cause hypo
CV benefits
- Decrease BP
- Nausea
- Pancreatisis
