Lec 45- Diabetes 1 Flashcards Preview

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Flashcards in Lec 45- Diabetes 1 Deck (48)
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1
Q

Diabetes mellitus and its treatment

A

-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

2
Q

Quick reminder: insulin is the main hormone controlling glucose homeostasis

A
  • 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

3
Q

Vital importance of glucose homeostasis (and if glucose gets to low)

A

-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

4
Q

If glucose gets to high

A
  • 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
5
Q

Origins of ketoacidosis

A
  • 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)
6
Q

Metabolic effects of insulin

A

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

7
Q

Diabetes Mellitus

A
  • 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
8
Q

Features of type 1 and type 2 diabetes

A

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

9
Q

Other types of diabetes

A
  • Gestational diabetes
  • Specidic genetic defects (monogenic diabetes) -Endocrinopathies)
  • Diseases of exocrine pancreas
  • Diabetes induced by drugs, chemical, infections
10
Q

Pathogensis of type 1 diabetes

A
  • 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)
11
Q

Immuno-pathogensis of type 1 diabetes

A

-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’

12
Q

Development of type 2 diabetes

A
  • 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)
13
Q

Diagnosis of diabetes

A

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
14
Q

Glycated Hb (HbA1c)

A
  • 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
15
Q

75g oral glucose tolerance test

A
  • 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
16
Q

Complications of diabetes (acute and chronic)

A

Acute

  • Hyperglycaemic coma: Type 1= ketoacidotic; Type 2= hyperosmolar
  • Hypoglycaemia (excess treatment)

Chronic

  • Microvascular: Retinopathy, nephropathy, neuropathy
  • Macrovascular: MI, stroke, Peripheral vascular dis
17
Q

Causes and consequences of type 1 diabetes

A

-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,

18
Q

Glucotoxicity causes microvascular complications

A

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)

19
Q
A
20
Q
A
21
Q

Diabetes prevalence in UK adults

A
  • Scotland= 271,312 = 5%
  • N ireland= 84,836= 5.4%
  • England= 2,913,538 = 6.2%
  • Wales= 183,348= 6.8%
22
Q

Burden of diabetes

A

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
23
Q

At risk of diabetes

A
  • 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
24
Q

Prevalance of diabetes in england by ethnic origin

A
  • This shows there is varying prevalence dependant on ethnicity
  • E.g. south asain and black carribean are more likely to get it
25
Q

Principles of diabetes management

A
  • 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
26
Q

Principles of diabetes management

A
  • Diagnosis
  • Care plan
  • Symptoms
  • Diet
  • Weight
  • Glucose
  • Co-morbidities
  • CV risk
  • Education
27
Q

Routine care

A
  • 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
28
Q

Management of diabetes- pharmacist

A
  • 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
29
Q

Diet management of diabetes

A

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
30
Q
A
31
Q
A
32
Q

Main blood glucose lowering agents UK

A

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

33
Q

Managing glucose control in type 2 diabetes

A

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

34
Q

Antidiabetic (glucose lowering) targets

A
  • 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)
35
Q

NICE guidline treatment algorithm

A
  • 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 –>
36
Q

Metformin- mode of action- intestine

A
  • 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

37
Q

Metformin- mode of action- Liver

A
  • 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
38
Q

Metformin- mode of action- muscle

A
  • Lower metformin exposure
  • Increase AMPK
  • Increase oxidative pathways

THIS CAUSES

  • Increase glucose uptake and oxidation
  • Increase glycogenesis
39
Q

Biguanide- Metformin- how it act, advantages and disadvantages

A

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
40
Q

Sulfonylureas and meglitinides

A
  • SUs: gliclizide
  • Stimulate insulin secretion; NB SUs last longer than glinides (prandial)
  • Weight gain
  • Risk of hypoglycaemia (important why driving)
41
Q

Thiazolidinediones- PPARy agonist

A
  • 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
42
Q

Alpha-glucosidase inhibitors (acarbose)

A
  • 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
43
Q

Incretin based therapies

A

-DPP4 inhibitors and GLP-1 receptors

DPP4 INHIBITORS

  • Sitagliptin
  • Vildagilptin

GLP-1 receptor agonists

  • Exenatide
  • Lixisenatide
44
Q

Incretin based therapies

A
  • This works by potentiating the effects of increasing insulin and decreasing glucagon
  • Decrease gastric empyting
  • Increase satiety (makes you feel full)
  • Decrease body weight
45
Q

Dipeptidyl peptidase-4 inhibitor (DPP-4)

A
  • Sitagliptin
  • doesnt cause hypoglycaemia
  • Potential CV benifites
  • Weight neutral
  • However pancreatitis
46
Q

SGLT-2 inhibitors

A
  • 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
47
Q

GLP-1 receptor agonists

A

-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
48
Q
A