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)
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
