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Endocrinology > week 2 > Flashcards

week 2 Flashcards

1
Q

what is the disease process of T2DM?

A

genetic+ environmental factors → insulin resistance → Compensatory beta-cell hyperplasia → failure to compensate (genetic predisposition)

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2
Q

what ethnicity is at a greater risk of T2DM?

A

east asian, indian

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3
Q

above what BMI for male and female is thee inc risk of T2DM?

A

24 Female; 25Male

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4
Q

in T2DM: insulin secretion

A

reduced

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5
Q

in T2DM: lipolysis

A

inc

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6
Q

in T2DM: glucose reabsorption in the kidney

A

inc

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7
Q

in T2DM: muscle glucose uptake

A

reduced

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8
Q

in T2DM: neurotransmitter

A

disturbance

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9
Q

in T2DM: hepatic glucose production

A

inc

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10
Q

in T2DM: incretin effect

A

reduced

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11
Q

in T2DM: glucagon

A

inc

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12
Q

how does the body adapt to insulin resistance? why does this fail?

A

inc Beta-cell mass.

genetic predisposition causes failure

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13
Q

why does weight reduction help T2DM

A

because its reduces insulin resistance and allows remaining Beta-cells to function with less.

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14
Q

how is theCVS risk address in T2DM?

A

statains and anti-hypertensives

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15
Q

management of type 2 DM

A

weight loss, exercise, metformin, statin, ACEi, diet/lifestyle, review appts.

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16
Q

how is metformin given initially

A

start 500mg and gradually increase due to GI side effects

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17
Q

what is the first line drug for type 2 DM?

A

metformin

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18
Q

how does metformin act

A

mechanism unclear.

reduces hepatic gluconeognesis and inc peripheral glucose uptake.

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19
Q

what are the adverse effect of metformin

A

GI and lactic acidosis (kidney, lung or liver disease beware)

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20
Q

what risk of three complications are reduced with good glucose control?

A

retinopathy, neuropathy, nephropathy.

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21
Q

what is seen as a good HbA1c

A

below 53

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22
Q

what is seen as a great/aggressive HbA1c

A

below 48

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23
Q

what are some second line drugs for type 2 DM?

A

SGLT2, glitazone, GLP-1R, SU, basal insulin, Gliptin (DPP-4 inhibitor)

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24
Q

what do incretins do?

A

stimulate decrease in blood glucose levels post-oral glucose (after eating).

((It is because of incretins and their amplifying effect that IV glucose has very shallow insulin spike compared to oral glucose))

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25
Q

what does obesity increase risk of?

A

T2DM

CVS: high BP, CAD, CHF, PE, Stroke

Cancer (many types)

OA, chronic back pain

Asthma, sleep apnoea, GB disease

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26
Q

what is the greatest contester to obesity - TV/cars or diet?

A

TV and cars

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27
Q

how does adipose tissue increase CVS risk?

A

adipose tissue is not inert, it has some similar properties to macrophages - key inflammatory cytokines found in adipose tissue can lead to atherosclerosis.

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28
Q

what is the function of leptin?

A

to tell body it has enough fat (energy stored as fat)

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29
Q

what happens if leptin deficient/lacking leptin receptors

A

inc appetite and weight gain

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30
Q

how is obesity treated?

A

diet, exersise, drugs, surgery

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31
Q

what drug can be used (as adjunct to dieting) to treat obesity?

A

Orlistat

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32
Q

how does Orlistat work?

A

inhibits lipase therefore blocking absorption of dietary fat in the gut

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33
Q

what are there procedures undergone in bariatric surgery?

A

gastic band, bypass or sleeve gastrectomy (long-term outcomes)

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34
Q

what is the best diet for weight loss?

A

low fat/low carbohydrate diets

success of diet depends on how committed patient is

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35
Q

why is it difficult to lose weight (after a little weight loss)?

A

because adaptive thermogenesis occurs

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36
Q

why does adaptive thermogenesis occur?

A

weight loss causes reduction in Resting Metabolic Rate(RMR) too but RMR falls MORE than expected making the next stage of weight loss more difficult

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37
Q

fat mass and non-fat mass make what

A

full body mass

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38
Q

what must occur in patient trying to lose weight

A

hypocalorific diet (intake must be less than usage) - the lower the RMR the harder to lose weight as the harder it is to keep intake under RMR

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39
Q

Name two advantages people with high metabolisms have

A

harder to gain weight

easier to lose weight (as RMR is higher easier to reach hypo calorific diet)

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40
Q

what are the risk factors for type2DM

A

obesity, age, genetics (ethrinicy, FHx), deprivation

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41
Q

what risk score is used to work out risk of type 2 DM in 10 years?

A

FINDRISC

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42
Q

what is important to consider/recommend in diet for diabetic (8 things)

A

Regular meals

Starchy CHO at each meal

Eat more fruit and veg

Cut down on fat, esp. saturated

Limit sugar / sugary foods

Reduce salt intake

Limit alcohol

Avoid diabetic foods

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43
Q

what is important in diabetes?: type 2 DM diet and aims

A

weight loss, smaller meals and snacks, physical activity, monitoring blood glucose and meds (if on insulin).

sustained weight loss/heatlhy weight alone can treat diabetes type 2

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44
Q

what is important in diabetes?: type 1 DM diet and aims

A

balancing insulin to CHO intake(carb counting), timing taking insulin, regular blood glucose monitoring.

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45
Q

what guide is used for macronutrient intake in diabetes

A

eatwell plate (similar to general population)

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46
Q

how to advise about sugars and sweeteners in diabetes.

A

no evidence that sugar has any greater impact than regular Carbohydrates - monitor OVERALL intake

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47
Q

what should be reduced by SIGN in non-pharamcological management of diabetes type 2

A

reduced energy dense foods (fat), fast foods, Alcohol and sedentary behaviour.

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48
Q

diet prescription by SIGN in non-pharamcological management of diabetes type 2

A

-600kcal deficit (tailored)

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49
Q

what is encouraged by SIGN in non-pharamcological management of diabetes type 2

A

Low energy density food and drinks

Mod to vig activity:

- Regular, tailored, provide support
- If diabetic with complications - medical review

Self-weighing (caution - people have unreal expectations 5-10% loss is good but people aim for more than that)

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50
Q

stress and illness can impact on gylcameic control . T/F

A

true

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51
Q

exercise can cause what in diabetic (type 1). what needs done

A

hypoglycaemia, adjust dosage

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52
Q

alcohol and diabetes problems [2] and pros [1]

A

hidden calories.

hypo can occur (esp if no food 12-16 hours post-drinking) - esp if using insulin or SU’s

moderate-alcohol drinking may lower risk of diabetes

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53
Q

what is the Glycaemic index (GI)?

A

measure of impact food has on blood glucose rise. [insufficient evidence to recommend]

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54
Q

what does diet do in type 1 and 2? (prevention or management)

A

1- management

2 prevention and management.

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55
Q

what re the chronic complications of DM?

A

Macrovascular:
IHD
Stroke

Microvascular:
Neuropathy
Nephropathy
Retinopathy

Cognitive dysfunction/ Dementia

Erectile Dysfunction

Psychiatric

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56
Q

what is diabetes the leading cause of? (3 things)

A

blindness, dialysis, amputation

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57
Q

what causes microvascular pathology?

A

hyperglycaemia [and hyperlipidaemia]

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58
Q

what do hyperglycaemia [and hyperlipidaemia] cause that subsequently leads to microvascular complications

A

AGE-RAGE, hypoxia, oxidative stress, inflammation, mitochondrial dysfunction

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59
Q

what are microvascular complications associated with DM

A

retinopathy, nephropathy, neuropathy

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60
Q

what are the 4 types of neuropathy that can occur (due to DM)

A

peripheral, autonomic, proximal, focal neuropathy

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61
Q

what is peripheral neuropathy?

A

pain/ loss of feeling in feet, hands

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62
Q

what is autonomic neuropathy

A

changes in bowel (gastroparesis), bladder function, sexual response, sweating, heart rate, blood pressure

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63
Q

what is proximal neuropathy

A

pain in the thighs, hips or buttocks leading to weakness in the legs (Amyotrophy)

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64
Q

what is focal neuropathy

A

sudden weakness in one nerve or a group of nerves causing muscle weakness or pain e.g. carpal tunnel, ulnar mono neuropathy, foot drop, bells palsy, cranial nerve palsy

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65
Q

what are the risk factors for developing neuropathy due to DM?

A

Increased length of diabetes

Poor glycaemic control

Type 1 diabetes > Type 2

High Cholesterol/ Lipids

Smoking

Alcohol

Inherited Traits (genes)

Mechanical Injury

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66
Q

what are the symptoms of peripheral neuropathy?

A

Distal symmetric or sensorimotor neuropathy

Numbness/insensitivity;Tingling/ burning; Sharp pains or cramps; Sensitivity to touch; Loss of balance and coordination

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67
Q

what are complications of peripheral neuropathy?

A

charcot foot, painless trauma (object, fracture), foot ulcer (not felt due to bad footwear)

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68
Q

treatment options for painful neuropathy

A

ATYPICAL ANALGESICS; amitriptyline (off-label), duloxetine, gabapentin, or pregabalin; combinations not recommended. Titrate up as needed.

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69
Q

treatment options for painful neuropathy if localised neuropathic pain?

A

topical Capsaicin Cream

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70
Q

what is Charcot Foot?

A

reduced sensation and reduced proprioception with trauma/damage to foot causing loss of joint position/ osteoarthropathy

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71
Q

focal neuropathy PC/signs

A

sudden, affects specific nerves,

EG: Inability to focus eye
Double vision
Aching behind eye
Bell’s palsy
Pain in thigh/ chest/ lower back/ pelvis
Pain on outside of foot
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72
Q

autonomic neuropathy affects what nerves?

A

affects nerves regulating HR + BP, as well as gastric motility, resp function, urination, sexual function and vision

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73
Q

what is AGE-RAGE

A

advanced glycation end products are proteins or lipids that become glycated as a result of exposure to sugars.
(factor in worsening of many degenerative diseases esp DM)

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74
Q

what problems in the digestive system can autonomic neuropathy cause?

A

gastric slowing/frequency (constipation and diarrhoea possible)

gastroparesis - slow stomach emptying causing persistent nausea, vomiting, bloatedness, los of appetite

oesophagus nerve damage causing dysphagia and wight loss

(all make BG levels hards to control)

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75
Q

how to treat gastroparesis causes by DM (autonomic neuropathy)

A

improve glycemic control

dietary (smaller portions with fibre - liquid meals if severe)

promotility durgs (metoclopramide) and anti-nausea meds (prochlorperazine). abdo pain (NSAID’s or tricyclic antidepressants).

botulinum toxin (into sphincter )

gastric pacemaker (severe)

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76
Q

how can sweat be affects in autonomic neuropathy

A

[nerves controlling sweating damaged so cannot regulate body temperature well] profuse nights sweats or while eating (gustatory sweating)

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77
Q

treatment for profuse nights sweats or gustatory sweating

A

Topical glycopyrrolate, clonidine, botulinum toxin

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78
Q

what can occur CVS-wise in autonomic neuropathy?

A

BP may drop sharply after sitting/standing (light headed/fainting)

HR may stay high instead of rising/falling to normal activities

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79
Q

investigations/diagnostic tools for neuropathy

A

nerve conduction studeis/EMG

HR variability

US

Gastric emptying studies

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80
Q

what is diabetic nephropathy?

A

A progressive kidney disease caused by damage to the capillaries in the kidneys’ glomeruli.

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81
Q

what is Diabetic Nephropathy characterised by?

A

nephrotic syndrome and diffuse scarring of the glomeruli

Microvascular changes- angiopathy of capillaries

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82
Q

what is Diabetic Nephropathy also known as

A

Kimmelsteil- Wilson Syndrome or Nodular Glomerulosclerosis

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83
Q

what are the Consequences

of Diabetic Nephropathy?

A

develop hypertension

relentless decline in renal function

accelerated vascular disease

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84
Q

how is Diabetic Nephropathy diagnosed?

A

micro/marcoalbuminuria

elevated creatine (severe)

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85
Q

what is used for Diabetic Nephropathy screening

A

urinary albumin creatinine ratio (ACR)

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86
Q

risk factors for neuropathy progression

A 
Hypertension
Cholesterol
Smoking
Glycaemic control
Albuminuria
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87
Q

what needs done if patient has microalbuminuria?

A

monitor creatine level, monitor fasting lipid profile

screen for retinopathy/PVD/high BP/IHD.

discourage smoking

investigate other range causes

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88
Q

treatment for diabetic nephropathy

A

BP (agressive management - 130/70)

good glycemic control (HbA1c around 53 mmol/mol)

Patients with microalbuminuria or proteinuria should be commenced on an ACEi/ARB

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89
Q

what is the commonest cause of kidney failure/dialysis?

A

DM

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90
Q

common diabetic eye problems

A

Diabetic Retinopathy

Cataract

Glaucoma

Acute hyperglycaemia- visual blurring (reversible)

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91
Q

what is a cataract

A

clouding of lens (deveops earlier in diabetics)

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92
Q

what is glaucoma

A

increase in fluid pressure in the eye leading to optic nerve damage. [2 x more common in diabetes]

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93
Q

what are the stages of retinopathy?

A

Mild non-proliferative (Background)

Moderate non-proliferative

Severe non-proliferative

Proliferative

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94
Q

macula/maculopathy is important why?

A

macula is the centre of the retina [responsible for what we see straight in front of us/ at the centre of our field of vision.]

The macula is very important as it gives us the vision needed for detailed activities such as reading and writing, and the ability to appreciate colour (cones)

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95
Q

terminology in diabetic retinopathy: haemorrages, cotton wool spots, hard exudates, IRMA?

A

Haemorrages: Dot/ Blot/ Flame

Cotton Wool Spots: Ischaemic Areas

Hard Exudates: Lipid break down products

IRMA: Intra-retinal microvascular abnormalities (abnormalities of blood vessels/ precursor to neovascularisation but blood vessels are patent (not leaking))

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96
Q

what is graded separately when it comes to Diabetic eye problems?

A

Retinopathy and Maculopathy are graded seperately

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97
Q

describe what would be seen on pre-proliferative retinopathy?

A

Haemorrages and Microaneurysms only

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98
Q

describe what would be seen on mild background retinopathy?

A

Micro aneurysms, hard exudates, haemorrages

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99
Q

describe what would be seen on Severe Non-proliferative retinopathy?

A

IRMA, venous beading, haemorrages

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100
Q

describe what would be seen on Severe Proliferative retinopathy?

A

New Vessel Formation

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101
Q

what does bleeding at the back of the eye due to DM cause? [Vitreous haemorrhage]

A

Sudden change in vision

Floaters

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102
Q

what can occur in severe proferative diabetic retinopathy?

A

Pre-retinal Fibrosis +/- traction retinal detachment;

Vitreous haemorrhage

other complications include secondary glaucoma and retinal detachment

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103
Q

how is macula degeneration assessed?

A

Optical Coherence Tomography (OCT)

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104
Q

treatment for diabetic retinopathy?

A

(prevention= good BG control, statins, anti-hypertensives + annual screening, )

laser, vitrectomy, anti-VEGF injections

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105
Q

what complication can occur due to vascular and neuropathy in DM?

A

ED (erectile dysfuction) - 50% of diabetic men

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106
Q

what are risk factors for ED?

A

DM, CRF, hepatic failure, MS, depression, other(vascular disease, low HDL, high cholesterol, hormonal deficiency)

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107
Q

causes of ED

A

DM [vascular and neuropathy contributions]

spinal cord injuries, pelvic/urogenital surgery

alcohol, substance abuse, smoking,

current medications

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108
Q

drugs that can cause ED?

A

anti-hypertensives (All capable - Common: thiazides and BB - Uncommon: CCB’s, alpha-adrenergic blockers, and ACEi)

CNS drugs (Antidepressants, tricyclics, SSRIs
Tranquilizers
Sedatives
Analgesics)

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109
Q

what should all patients with diabetes should have at least annual screening of?

A

eyes, feet and kidneys [ACR/ U and Es]

-remember to think about ED

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110
Q

what may early detection prevent and reduce rates of?

A

prevent progression and reduce rates of blindness, amputation, foot ulcer and kidney failure (dialysis)

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111
Q

if what three things are controlled, then the risk of complications can be reduced substantially. what are the three factors

A

BG
BP
Blood lipid

(good control of all three lower complication risk)

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112
Q

name a buguanide

A

metfromin

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113
Q

give three examples of sulphonureas

A

Glicazide
Glibenclamide
Glimeparide

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114
Q

name a Thiazolidinedione

A

Pioglitazone

Rosiglitazone - withdrawn

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115
Q

(good )effects of metformin

A

Hyperglycaemia management:

Hypoglycaemia: (very rare when used as mono therapy)

Often reduces weight

Prevents microvascular/macrvascular complications:

(reduces trigylcerides + LDL + BP, safe in pregncacy, helps NAFLD, PCOS)

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116
Q

adverse effect of metformin

A

Common: GI :
Anorexia, nausea, vomiting, diarrhoea, abdo pain, [metal] taste disturbance
GI side effects in up to 25%; only 5% cannot tolerate the drug

Interference with vitamin B12 and folic acid absorption (anaemia is rare)

Lactic acidosis
rare unless renal/lung/heart disease

(Liver failure + rash very rare)

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117
Q

practical issues: metformin (how to start, when to stop, when to be cautious)

A

start low go slow for GI side effects,

caution in Cardio/resp/Renal patients.

half dose if eGFR 30-45 and stop is < 30

discontinue if advanced cirrhosis/liver failure

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118
Q

what is the first line agent for T2DM?

A

metformin

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119
Q

what are examples of 1 and 2 generation Sulphonylureas (SU)?

A

1st generation (rarely used any more):
Chlorpropramide
Tolbutamide

2nd generation (shorter acting):
Glicazide
Glibenclamide/glyburide
Glimepiride

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120
Q

what are the effects of SUs?

A

manage hyperglycaemia (potently), prevent microvascular complications

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121
Q

SU adverse effects

A

Hypoglycaemia - (Particular care in elderly/frail, alcohol excess, liver disease)

Weight gain

GI upset, headache

Rarely hypersensitivity, blood dyscrasias and liver dysfunction

Avoid in severe renal or hepatic failure

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122
Q

when are SU used?

A

second line after metformin

those intolerant to metformin

acute circumstances for gylcaemic control (takes 48hrs to work whereas metformin takes a few weeks )

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123
Q

TZD’s/Thiazolidinediones act in what way?

A

PPARγ agonists

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124
Q

TZD effects (good)

A

Hyperglycaemia management:

Hypoglycaemia not common

Improvement in microalbuminuria (no vascualr improvement however)

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125
Q

TZD effects [bad]

A

Hypoglycaemia (if used with SU)

Weight Effect: inevitable
due to increase in subcutaneous (but not visceral) fat and fluid retention

Heart Failure

bone density affects (# rate)

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126
Q

who are TZD’s not given to? why?

A

over 65’s (# risk)

HF patients (Fluid retention results in near doubling of risk of admission with heart failure (risk still low in non-elderly without pre-existing HF))

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127
Q

what type of drugs act on the incretin pathway?

A

GLP-1R agonists

DPP-4 inhibitors

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128
Q

what is the incretin effect

A

less insulin produced off IV rather than oral glucose (due to incretins from gut being transported in blood to pancreas)

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129
Q

why is hypoglycemia more common in SU?

A

because B cells continually produce insulin.

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130
Q

what two incretins (intestinal secretion of insulin) molecules are there and what cells are they from?

A

GIP ;Kcells

GLP-1; L cell

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131
Q

example(s) of a GLP -1R agonist

A

Exenatide

[Exendin, Liraglutide, Lixisenatide]

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132
Q

benefits of GLP-1R agonist

A

Promote insulin secretion from pancreas without hypoglycaemia

Suppress glucagon (which is increased in T2DM)

Decrease gastric emptying – early satiety

Act on hypothalamus – reduce appetite – resulting weight loss (~3kg

[reduced CVS outcomes, death and improves renal disease]

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133
Q

disadvantages of GLP-1R agonist

A

Nausea – usually resolves in most by 6-8 weeks

Injectable

pancreatits?

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134
Q

DPP-4 inhibitors example of?

A

Vildagliptin, Sitagliptin, Saxagliptin, Linagliptin

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135
Q

why are DPP-4i’s less potent than GLP-1 mimetics?

A

as can only work on what’s there and GLP-1 levels are low in T2DM

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136
Q

pro’s of DPP-4i’s

A

Promote insulin secretion from pancreas without hypoglycaemia

Suppress glucagon (which is increased in T2DM)

Weight neutral

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137
Q

cons of DPP-4i’s

A

Very limited side effects

Not that potent

No weight loss

Pancreatitis?

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138
Q

examples of SGLT2 inhibitor (3)

A

CANAGLIFLOZIN

EMPAGLIFLOZIN

DAPAGLIFLOZIN

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139
Q

what do SGLT2 inhibitors do/how they work?

A

decrease uptake of sugar in kindness glomerulus by about one quarter (pee out sugar!)

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140
Q

pro’s of SGLT2i’s

A

weight loss,

blood sugar control,

reduced CVS events, death and hospitalisation for HF

benefical for most renal outcomes

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141
Q

cons of SGLT2 i’s

A

sugar in urine causes PC of T2DM symptoms (INC THRUSH AND INC URINE INFECTIONS)

doesn’t work well if kidney damages (eGFR <60 not used)

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142
Q

which T2DM drugs give CVS benefit?

A

Empagliflozin (and probably all SGLT2i), Liraglutide
Semaglutide, Pioglitazone.

slightly metformin and exenatide

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143
Q

which T2DM drugs are neutral in CVS benefit?

A

Lixisenatide, DPP4i, SU

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144
Q

which T2DM drug is harmful in CVS

A

Rosiglitazone (discontinued)

145
Q

what type of insulin regime is used in T2DM compared to T1DM?

A

basal, rather than basal-bolus.

146
Q

when is insulin prescribed to T2DM patient?

A

Usually as people fail on non-insulin therapies: (3 drugs and poor glycemic control)

147
Q

use of insulin in T2 Diabetic

A

Once daily NPH Insulin (24 hrs) is added to Metformin (+/- SU).

If this is ineffective or becomes so then change to bd NPH insulin or mixed insulin (Humulin M3)

148
Q

what are the insulin Secretagogues?

A

SU, DPP4i’s, GLP-1RAgonists.

149
Q

what are the insulin sensitisers?

A

TZD’s

metformin (sort of)

150
Q

what T2DM drugs are neither insulin sensitisers or Secretagogues?

A

SGLT2i’s

151
Q

give a rough run-through of treatment of T2DM?

A

1st (metformin), 2nd line (SU, TZD, DPP4,SGLT2s), 3rd line (GLP-1RA), 4th (insulin)

152
Q

which type 2 DM drug(s) cause weight to stay neutral?

A

DDP4, SGLT2

153
Q

which type 2 DM drugs cause weight loss?

A

GLP-1R!, metformin

154
Q

which type 2 DM drugs cause weight gain?

A

SU, TZD’s

155
Q

which T2DM drug(s) is injectable?

A

GLP-R A

[Liraglutide/Exenatide/Lixezenatide]

also insulin

156
Q

which T2DM drug(s) give renal protection?

A

SGLT2i’s

157
Q

which T2DM drug(s) cause thrush and UTI’s?

A

SGLT2i’s

158
Q

which T2DM drug(s) don’t cause hypo’s

A

DPP-4, SGLT2i

159
Q

which T2DM drug(s) cause hypos

A

SU

160
Q

which T2DM drug(s) help CVS risk?

A

metformin, SGLT2i, GLP-1R

161
Q

which second line T2DM drug(s) are potent?

A

SU, TZD’s

162
Q

HF and inc#s are associated with which T2DM drug(s)

A

TZD’s

163
Q

potent action, weight gin and hypos are associated with which T2DM drug(s)

A

SU

164
Q

injectable, Weight loss causing,CV Benefit and possible pancreatic inflammation are associated with which T2DM drug(s)

A

GLP-1R

165
Q

Weight neutral, No hypos, possible pancreatitis

are associated with which T2DM drug(s)

A

DPP-4 i

166
Q

a Weight neutral, CV benefiting, Renal protecting, No hypos drug with Thrush/UTI associated is that T2DM drug?

A

SGLT2i

167
Q

85 year old man with T2DM since age 80; BMI 29

HbA1c 75; eGFR 40

Treatment – Metformin 1g bd, Glibenclamide 5mg od

A)what to do?

A

Half metformin,

stop glib due to concerns of hypo in elderly.

Relaxed HbA1c target (microvascualr disease not problem as will die of MI/cancer).

Give a DDP-4i.

168
Q

50 year old man with T2DM for 2 years

HbA1c 58; eGFR >60

Treatment – Metformin 1g bd
BMI of a)30, b)45

A

Lower HbA1c target below 53(48).

BMI 30 – SU.
BMI 45- SGLT2 or injectible GLP-1R agonists

169
Q

70 year old woman with T2DM since age 60; ‘bad COPD’; MI and Angina

HbA1c 75; eGFR 55. BMI 32

Treatment – Metformin 1g bd, Gliclazide 80mg bd; Pioglitazone 30mg od

what to do?

A

Insulin or Empagliflozin as good for heart disease.

stop Pioglitazoe (as weight gain) and shouldn’t have >3 drugs

170
Q

70 year old woman with T2DM since age 60

HbA1c 64; eGFR 25. BMI 32

Treatment – Metformin 1g bd, Gliclazide 80mg bd; Sitagliptin 100mg od

what to do?

A

Metformin stop.

(Sitagliptin – reduce dose due to renal problems)

Insulin treatment as due to declining kindye function other drugs cannot be used.

171
Q

how do you reduced CVS risk in T2DM?

A

anti-hypertensive,

lower lipids (statins, Ezetimibe, [PCSK9i])

172
Q

what must be checked when prescibig insulin to a NEW patient?

A

occupation (HGV license suspended until adequate control demonstrated)

173
Q

what is a normal creatine level? what does above this mean?

A

below 110 (depends on age/sex) - above = renal failure

174
Q

what is eGFR?

A

estimate Glomerular Filtration Rate (falls in kidney disease/elderly)

175
Q

why can metformin cause lactic acidosis?

A

poor kidney function stops metformin being exreted so get accumulation

176
Q

what total Chol and LDL should be aimed for in post-MI patient?

A

total <4

LDL <2

177
Q

insulin patient keeps gaining weight and then having hypos when trying to diet? treatment?

A

reduce (BUT DONT STOP) insulin

178
Q

what can be done for patient who is fed up of doing blood glucoses prick tests?

A

CGM

reduce number of times a day

179
Q

drinking on insulin?

A

okay but not too much. check BG before bed,

have CHO snack before bed

180
Q

I’ve woken up in the morning vomiting – I can’t keep anything down. Should I stop my insulin? I’m on Novomix30, 26 units, twice daily

A

No don’t stop your insulin or DKA, follow sick day rules.

(when unwell normally need insulin due to outpouring of hormones (cortisol and adrenaline) - often diabetics can tell as day or 2 before as get hyper. )

181
Q

Can people on insulin have sex? Am I likely to get a hypo – I often have hypos during the night

A

Yes, treat it the same as exercise.

182
Q

what to do if insulin injection has leaked out?

A

don’t give another - carefully monitoring and assess if small booster is needed

183
Q

taken too much insulin?

A

admit to hospital if gross (10x amount)

if small then CHO snack and check blood hourly (have sugar PRN)

184
Q

why does exersise need reduced insulin dose?

A

can cause hypo.

bc Inc exercise causes inc usage of glycogen in muscles and post-exercise, anabolism/ uptake in muscles. This means insulin acts more/more effective so reduce insulin to avoid hypo

185
Q

definition of DKA

A

a disordered metabolic state that usually occurs in the context of an absolute or relative insulin deficiency accompanied by an increase in the counter-regulatory hormones i.e. glucagon, adrenaline, cortisol and growth hormone

186
Q

describe the pathophysiology of DKA (roughly)

A

insulin deficiency→stress hormone activation→lipolysis and hyperglycaemia→Osmotic diuresis occurs→hyperosmolar

187
Q

what are the causes patients presenting with DKA (4)

A

new Type1,

poorly controlled Type1,

Not type 1,

Drug/alcohol associated.

188
Q

how is DKA diagnosed biochemically? (3)

A

Ketonaemia > 3mmol /L, or significant ketonuria (>2+ on standard urine stick)

Blood glucose > 11.0 mmol /L or known diabetes (NB euglycaemic DKA)

Bicarbonate < 15 mmol /L or venous pH < 7.3

[[[Basically diagnosed by: high blood sugar, low blood pH, and ketoacids in either the blood or urine]]]

189
Q

what are common contributions to DKA(inc risk of having DKA)?(4)

A

infection.

illicit drugs/alcohol.

non-adhereance to treatment

newly diagnosed diabetes

190
Q

typical symptoms and sings of DKA?

A

Osmotic related:

  • thirst+polyuria
  • dehydration

ketone body related:

  • flushing, vomiting, abdo pain and tenderness.
  • SOB/Kussmaul’s respiration
  • ketone on breath

associated conditions:
-underlying sepsis
-gastroenteritis
(coma uncommon)

191
Q

classical biochemistry at presentation of DKA (5 markers)

A

glucose: average around 40mmol/L
potassium: ↑5.5mmol/L, beware low K+ as leads to arrhythmia

↑ creatine (often)

↓ sodium (often)

↑ lacate (very common)

192
Q

glucose levels in DKA at presentation

A

average 40 (normally >6)

from 10(eugylcaemic ketosis) to 100mmol/L

193
Q

electrolyte loss occurs in DKA. what electrolyte in particular?

A

K+ (bad as hypokalemia causes arrhythmia, VF, and cardiac arrest)

194
Q

what ketones are measured: in blood, urine?

A

blood = βhydroxybutarate

Urine = acetoacetate

[blood preferred as urine testing takes too long to get results]

195
Q

what is the bicarbonate level to diagnose: DKA, severe DKA?

A

< 15 mmol /L or venous pH < 7.3 = DKA

<10 bicarbonate in most severe cases

196
Q

what ‘innocuous’ biochemical markers can be raised in DKA? (2 things)

A

amylase - very frequently raised, doesn’t necessarily mean pancreatitis [can be salivary in origin]

WCC (average around 25, doesn’t always infer infection) - treat DKA then see it go down/address it

197
Q

what does DM have association with disease-wise? (think GI disease)

A

coeliac’s (5% of coeliacs have DM)

198
Q

DKA in pregnancy give increase risk of what?

A

stillbirth (50%)

199
Q

what can be lost in DKA?

A

FLuid, Na+, K+, phopshate

200
Q

risk of complications from DKA in adults? common and less common (3 of each)

A

COMMON-aspiration pneumonia, ARDS, hypokalaemia

RARER-sepsis, thrombo-embolic risk, acute gastric dilation

201
Q

DKA in children specific complication

A

cerebral oedema

202
Q

management of DKA (3 general points)

A

in hospital (in HDU)

replace losses

address risks

203
Q

when managing DKA replacing losses is important. what must be replaced? (3 done, 2 not done)

A

FLUID- initally saline but if glucose falls to about 15 then switch to dextrose

INSULIN

K+

[phosphate and bicarbonate rarely replaced ]

204
Q

when managing DKA addressing risks is important. what must be addressed?? (4)

A

NG tube required?

Monitor K+

Prescribe prophylactic LMWH

Source sepsis: CXR, Blood Culture, MSSU +/- viral titres, etc.

205
Q

what can be used to monitor ketones in DKA patients (blood)? what is normal range in blood?

A

Optium meter - measures up to 8mmol/L

< 0.6 mmol/L normal

206
Q

preventing recurrence of DKA is important.hows this done?

A

address why it happened.

sick-day rules?

give patient ketone meter

clinic flow up/alert GP

207
Q

what is HHS (hyperglycaemic hypersomolar syndrome)

A

a complication of DM in which high BG results in high osmolarity without significant ketoacidosis.

208
Q

HHS typical features of patient

A

undiagnosed/diet controlled type 2 DM (often), older individuals/younger from non-caucasian groups.

high refined CHO intake pre-event. has risk associations (CVS event, sepsis, medications)

209
Q

what medications are associated to inc risk of HHS?

A

GLUCOCORTICOIDS

thiazides

210
Q

definition of HHS

A

hypovolaemia

hyperglycaemia [>30] without significant acidosis/ketonaemia

hyperosmolar

211
Q

hyperosmolar defined as what?

A

osmolality >320 mosmol/kg

212
Q

typical biochemistry of HHS

A

higher glucose than DKA (around 60 average)

significant renal impairment.

raised NA+ often

significant ↑osmolarity - around 400 (i.e. significant dehydration).

less ketonaemia/acidotic than DKA

213
Q

formula for osmolarity?

normal range for osmolality

A

Osmolality=2x[Na+/-K] + Urea + Glucose

Normal osmolality 285 to 295

214
Q

HHS investigations

A

venous glucose

Na+, K+, urea, Creat (eGFR).

ABG: pH. Bicarbonate.

urinary ketones

215
Q

compare DKA and HHS: age, Type of DM.cause. precipitating factors, mortality, treatemnt

A

DKA: younger, Type1, insulin defiency. insulin omission, <2%. insulin = treatment

HHS: older, Type2, due to diuretic/steroids/fizzy drinks. new diagnoses or infection. 10% mortality. treatment =diet/drugs.

216
Q

differences in treating HHS vs DKA

A

fluids - more cautious as inc risk of fluid overload

insulin - HHS may not require insulin, and patients are more sensitive so give slower

sodium - avoid rpaid fluctuations

co-morbidiites - more likely (screen for vascular event,sepsis = LMWH for all unless contraindicated)

217
Q

where does lactate originate from?

A

red cells, skeletal muscle mainly

also brain and renal medulla

218
Q

what is the end product of anaerobic metabolism of glucose?

A

lactate (generated in cytoplasm)

219
Q

how is lactate cleared?

A

Clearance requires hepatic uptake and aerobic conversion to pyruvate then glucose.

220
Q

lactic acidosis and hyperlactataemia

A

need to distinguish between hyperlactataemia and lactic acidosis.

Normal range lactate is 0.6 to 1.2 mmol/L

> 5mmol/L more likely acidosis

221
Q

lactic acidosis: types, causes

A

A: associated with tissue hypoxaemia (infracted tissue, cariogenic shock, hypovolaemic shock - sepsis/haemorrage)

B: may occur in liver disease, leukaemia states, associated with DM (10% DKA have lactate >5mmol/L; esp with metformin in renal failure/severe illness states). Also consider rare inherited metabolic conditions if well and non-diabetic

222
Q

define hyperlactataemia

define lactic acidosis

A

mild/moderate lactate in blood 2-4mmol/L without metabolic acidosis

> 5 mmol/L wit metabolic acidosis

223
Q

Pc of lactic acidosis

A

Hyperventilation
Mental confusion
Stupor or coma if severe

224
Q

lab findings in lactic acidosis

A 
Reduced bicarbonate
Raised anion gap 
Glucose variable – [often] raised
Absence of ketonaemia
Raised phosphate
225
Q

what is the anion gap?

A

[Na+ + K+) – (HCO3 + Cl-)

226
Q

what are some causes of a raised anion gap?

A

lactica acidsosi

[Other causes: dka, starvation, uraemia, alcohol, ethylene glycol, methanol, salicylate or paraldehyde poisoning.]

227
Q

what makes up difference in anion gap?

A

Negatively charged proteins, sulphate and phosphate and some organic acids make up the difference

228
Q

what is normal anion gap range?

A

The normal range is 10 to 18 mmol/L

229
Q

why is the anion gap useful?

A

Useful in determining the cause of an acidosis:

i.e. those conditions with a normal anion gap and those with a high anion gap

230
Q

treatment of lactic acidosis

A

Underlying condition: -Fluids, Antibiotics

Withdraw offending medication

231
Q

Alcohol-induced ketoacidosis PC

A

heavy alcohol intake for many years;

recurrent vomiting.

dry and difficult to rouse

hypotensive

tachnpoeic

232
Q

treatment for Alcohol-induced ketoacidosis

A
  • Pabrinex – high dose vitamins.
  • IV fluids particularly dextrose.
  • On occasion insulin may be required.

Address alcohol dependency

233
Q

what should be considered/assessed before elective surgery?

A

Anaesthetic risk: Cardiac,
Autonomic dysfunction,
Should also include foot risk

Glycaemic control: HbA1c at least < 70 mmol/mol

put first on surgical list

234
Q

hospital inpatient target and accepted ranges

A

6-10mmol/L targeted.

accepting a range of 4-12mmol/L (individualise targets - end of life/ severely disables less important to control)

235
Q

emergency surgery in diabetic

A

inc risk as unplanned.

recognise complications (micro/macrovascular).

attention to K+ (esp if glucose is high)

post-op sepsis risk if control poor

foot car issues post-op

236
Q

what to do for diabetic foot care?

A

check, protect, refer

237
Q

what is used to counteract hypoglycaemia?

A

hypo box. (lucozade, glucose solution, dextrogel)

238
Q

HHS is much rarer + has higher mortality than DKA. T/F?

A

Ture

239
Q

high ketones in blood suggest what diseases/conditions ?

A

severe DKA, eugylcaemic DKA, Alcohol-induced

Keto-acidosis.

240
Q

dehydration occurs in which diseases/conditions?

A

severe DKA, eugylcaemic DKA, Alcohol-induced

KA, HHS

241
Q

what is normal blood pH?

A

7.35-7.45

242
Q

what conditions cause lowering of pH?

A

severe DKA, eugylcaemic DKA, alcoholic KA <7.2

lactic acidosis <7.35

243
Q

SOsm (serum osmolarity) is increased in what condition(s)

A

HHS ( >320)

[severe DKA/alcohol KA = normal/variable]

244
Q

Out of: severe DKA, eugylcaemic DKA, Alcohol-induced

KA, HHS, lactic acidosis; which has raised glucose [in defending order]

A

HHS(50-100), DKA(25-100), euglycaemic DKA(<15), lactic acidosis/alcohol KA (normal).

245
Q

why does eugylcaemic DKA occur?

A

lack of glycogen storage in liver. poor injectors but regular (teenage girls worried about weight) and alcoholic liver disease. gradual would up in ketones in blood and get wrong the BG of 10-15 with KA

246
Q

medical complications of obesity

A

DM. Macrovascular, OA, back pain, cancers (13 types inc breast and bowel) GB disease, NAFLD, high lipids/BP, phlebitis, gout, skin, pancreatitis, , sleep apnoea

247
Q

what is used to assess weight in adults?

A

BMI (asain pop need lower BMI).

Waist circumference

248
Q

what is used to assess weight in kids?

A

centile cutoffs (91st = overweight)

249
Q

obesity prevelence and trends

A

64% of adult population overweight /obese

childhood increasing (20% Primary 1’s overweight)

obesity on increase

250
Q

obesity risk factors

A

inc age, deprived, inactive, pregnant, ethnic, low metabolism, obese children with obese parents,, quitting smoking.

251
Q

lifestyle factors affecting obesity (3)

A

regular exercise,

low density foods

having been breastfed

252
Q

patient under 30 suspecting DM DD?

A 
TYpe1 - usually
something weird (MODY/funny syndome/endocrinopathy)
Type2 - if none of these
253
Q

what does MODY stand for?

A

Maturity onset diabetes of the young

254
Q

genetics of MODY

A

autosomal dominant

255
Q

age of onset for MODY

A

usually before 25

256
Q

why is recognising MODY important?

A

bc it is an NON-INSULIN DEPENDANT DIABETES

257
Q

what are the 3 categories of MODY?

A

glucokinase mutation

transcription factors mutation (HNF1a,beta/4alpha+others)

MODY x (unknown gene)

258
Q

what is commonest and second commonest MODY?

A

HNF1alpha.

Glucokinase

259
Q

what reaction does glucokinase catalyse?

A

glucose into (gluco-6-phosphate)

260
Q

what does a glucokinase mutation MODY cause?

A

inc normal BG stepping is higher (7mmol/L not 5mmol/L). - curve right shifted.

everything works fine (insulin prodcued okay), just setpoint is high

261
Q

how do you differentiate between MODY and other diabetes; and which type of MODY it is? who other than patient should be genetically tested?

A

genetic testing (also tells type of MODY).

OGTT (high BG but steady in GCK; higher and rising in HNF)

family members as FHx strong

262
Q

GCK and HNF differences?

age of onset, disease course, complication risk, treatment

A

GCK - onset from birth, Stable hyperglycaemia/non-porgressive disease,
Diet treatment (NO NEED FOR INSULIN)
Complications rare

HNF
Adolescence/young adult onset
Progressive hyperglycaemia
1/3 diet, 1/3 tablets, 1/3 Insulin
Complications frequent
263
Q

when is GCK mutation relevant? why?

A

pregnancy. if mother and baby do not both carry mutation then environment has too high/low sugar. Also if undiagnosed and controlled GCK in baby with mutation then created hypo environment.

264
Q

HNF1alpha has very good response to what drug? why?

A

SU’s/Gliclazide (because deficit is in GLUT2, SU’s ramp insulin production up later in cycle so mutation is not relevent - acts like ATP from mitochondria on Katp channel, so no need for ATP to come from Mitochondria)

265
Q

how can C-peptide be used to find undiagnosed MDOY in long-term type 1 DM patients?

A

after 5 years insulin production for type 1’s stops (so no C-peptide). if c-peptide present after this time then suspect MODY

266
Q

how many cases of DM in under 30’s is MODY?

A

3%

267
Q

what is neonatal diabetes?

A

monogenic form of diabetes that occurs in the first 3/6 months of life. (<1 year DM more likely neonatal that T1DM).

268
Q

what do all patient with NDM require? how common is it?

A

Requires insulin treatment within first 3 months of life

rare – 1 in 200 000 live births

269
Q

what are the two type of NDM?

A

transient and permanent NDM [TNDM + PNDM]

270
Q

TNDM: when is it diagnosed?,treatment ?

A

Diabetes usually diagnosed < 1 week

Resolves median 12 weeks - stop insulin

271
Q

PNDM: when is it diagnosed?treatment ?

A

Diabetes usually diagnosed 0 - 6 weeks

Lifelong treatment with
insulin or SU’s (try SU’s first and insulin may not be necessary)

272
Q

what drug is particularly effective in PNDM? why?

A

SU’s

because it closes Katp, so membrane gets depolarised, calcium influx occurs and insulin is secreted.

273
Q

what mutations can occur in NDM?

A

potassium channel gene mutations (patients can transfer of lifelong insulin to SU’s)

274
Q

treatment of GCK and HNF1alpha?

A

HNF1A are SU sensitive;

GCK do not require treatment

275
Q

commonest cause of INCIDENTAL persistent high BG in paediatric?

A

GCKmutations,

[[[then type 1 DM, then IGT (impaired glucose tolerance/Pre-diabetes) then other mutations ]]]

276
Q

what is the largest largest component of the glycated hemoglobins (60-80%)

A

HbA1c

277
Q

how is HbA1c formed?

A

by non-enzymatic glycation of haemoglobin on exposure to glucose

278
Q

why can HbA1c be used to evaluate BG control?

limitations of HbA1c?

A

Increases in a predictable way in response to prevailing glucose
(over 6-8weeks; life of RBC 100 days; not quite prefect as last week has > affect on result)

limited as variation not measured (only average - gives photograph not film like CGM)

279
Q

what values of HbA1c indicate normal, pre-diabtetes and DM?

A

<42 (<6%)
42-27 (6%-6.4%)
>48 (>6.5%)

280
Q

what is target HbA1c?

A

53 for good control, 48 for great/strict control

281
Q

what are the pro’s and cons of glucose monitoring?

A

Benefits: -Glucose control, Symptoms/Lifestyle/exercise
Carbohydrate counting

Problems: Painful,Intrusive,Discriminating

282
Q

target BG for children with T1DM?

A

on waking and before meals: 4–7mmol/l

after meals: 5–9mmol/l

283
Q

target BG for adults with T1DM?

A

on waking: 5–7mmol/l

before meals at other times of the day: 4–7mmol/l

90 minutes after meals: 5–9mmol/l.

284
Q

target BG for T2DM?

A

before meals: 4–7mmol/l

two hours after meals: less than 8.5mmol/l.

285
Q

targets for pregnant women with Diabetes?

A

fasting: below 5.3mmol/l

and
1 hour after meals: below 7.8mmol/l or
2 hours after meals: below 6.4mmol/l

286
Q

CGM vs SMBG (pro’s vs cons of CGM)

A

CGM pros= more detailed.

Cons= cost, accuracy(measured interstitial fluid glucose not blood so Hypo and delay not recognised) and acceptability difficult (physical device under skin)

287
Q

Abbott Free Style Libre

A

flash glucose monitoring - swipe phone to give BG.

288
Q

typical sequence of events of a hypo

A

hunger then weakness/fatigue then anxiety (with shaking and profuse sweating)

289
Q

PC of a hypo (all possible symptoms )

A 
hunger, 
weakness/fatigue
anxiety
shaking
profuse sweating
dizziness
fast HR
impaired vision
headache
irritable
290
Q

what is a severe hypo seen as clinically?

A

Hypoglycemia that leads to seizures, unconsciousness or the need for external assistance.

291
Q

what is the alert value for hypo? what is the value for emergency/severe hypo?

A

4mmol/L (4 is the floor)

3mmol/L

292
Q

what is the process of a hypo in normal person?

A

BG drops so stop making endogenous insulin (

293
Q

what is the process of a hypo in diabetic person?

A

endogenous insulin can’t be stopped (as injected), glucagon not produced and adrenaline works at lower BG level. gives smaller window for corrective actions/symptoms until cognitive dysfunction.

294
Q

why do regulatary hormones in hypo in Diabetics not work as effectively??

A

glucagon - phenomenon, stop making after 5 years post-diagnosis.

adenaline - starts to work at lower BG level.

295
Q

what happens to rate of Hypos as T1DM progresses? why?

A

rate of hypo’s inc, also impaired awareness of Hypos

because body adapts to see hypo as less harmful (protection), this causes less damage to the cells - effective building tolerance/preconditioning occurs. [Every hypo leads to decreased awareness of next hypo]

296
Q

when is most common time to have hypo? why?

A

at night (>50%).

adrenaline response not as effective as when awake

297
Q

what is important to do (legally) if patient has impaired awareness of Hypos

A

driving license needs assessed

298
Q

how is impaired awareness of Hypo’s diagnosed?

A

symptom-free until < 3mmol/L.

severe hypo suffered

299
Q

BG levels for a hypo in normal, Type1, type 2 patients?

A

normal - <4

Type 1 - < normal as impaired awareness

type 2 - higher; <7mmol/L can be hypo

300
Q

treatment for hypo (non-severe)

A

CHO (15-20g) rechecking BG every 15mins. if still low more CHO; if resolved then onto next planned meal

301
Q

treatment for severe Hypo

A

HOME:Glucagon - 1mg injection. regain consciousness in 5-15mins; may experience nausea/vomiting.

HOSPITAL: dextrose (IV)

302
Q

therapeutic implications for hypo (long-term care)

A

Intensive Insulin Therapy

Insulin analogues/CSII

CGM

Cognitive behaviour therapy

Pancreas Transplantation (islet cell)

303
Q

rare contributors to hypo risk

A

hypopituitarism, addison + (many) others

304
Q

addison presentation

A

low glucose + vomiting, in young thin male.

305
Q

type 1 DM: factors/predictors

A

certain HLA types, FHx, autoantibody positive

306
Q

insulin conc in T1/2DM

A

type1 - low

type 2- high, normal or low.

307
Q

C-peptide is a marker for what?

A

marker of endogenous insulin (measuring insulin includes), preserved in type 2 (unless low blood sugar - insulin not produced) lost in type 1 (lose after 5 years).

308
Q

polyuria, polydipsia, wight loss (failure to thrive) is classic triad for what condition?

A

type 1 DM PC

309
Q

causes of Hypo? (3)

A

insulin/CHO imbalance (too much insulin or not eating enough), alcohol, exercise

310
Q

what does illness do to BG?

A

inc (stress hormones cause rise in BG (cortisol, adrenaline) patients often need more short-acting insulin that usual).

311
Q

what does alcohol do to your blood sugar?

A

beer- inc(as lots of CHO); may need inc short-acting insulin

gin/vodka -reduced (no CHO)

inhibits gluconeogenesis in liver (counter regulatory response) and so hypo risk in morning. - need reduction in basal insulin

312
Q

what does exercise do to your blood sugar?

A

high-intensity/sprint - not depleting glucose. (in adrenaline/cortisol)

prolonged/long-distance - depletion of glucose stores. get hypo at night/sleep so reduced background insulin (muscles/liver)

313
Q

T1DM with past good control now struggling

A

another AID developed (people commonly have overlap)

EG: addisons, coelics…

314
Q

how to investigate DKA? (3things)

A

BG, blood ketones, ABG. (takes 5 mins)

315
Q

DKA treatment

A

fluid (about 8L on average - 1L quite quickly then inc time).
K+ deficiency (but is high because of degree of acidosis - insulin drive K+ into cell) give K+
give insulin according to blood sugar

316
Q

glitazones/TZD/Thiazolidinedione act how?

A

PPARgamma

317
Q

what ways do T2DM drugs work? (4) which drugs?

A

inc insulin secretion (SU, incretin mimics, glinides, DPP-4i’s)

decrease insulin resistant and reducing hepatic glucose output (biguanides, glitazones/TZD’s)

slowing glucose absorption from the GI tract (α-glucosidase inhibitors)

enhancing glucose excretion by the kidney (SGLT2i’s)

318
Q

what are insulin dependant and insulin independent drugs MOA in T2DM?

A

inc insulin secretion + decrease insulin resistant and reducing hepatic glucose output = dependant (all except below)

slowing glucose absorption from the GI tract + enhancing glucose excretion by the kidney = independent (α-glucosidase inhibitors, SGLT2i’s)

319
Q

GLUT 2 and GLUT 4 where are they found and how are they different?

A

GLUT 2 - glucose uptake in Beta-cells, constantly there

GLUT 4 - glucose uptake in target tissues in response to insulin, move to membrane

320
Q

rough pathway of insulin secretion?

A

high BG → in diffusion of glucose via GLUT2 into cell →phospharation by glucokinase to gluc-6-P →glycolysis → mitochondria → inc ATP/ADP ration in cell CLOSES Katp. →membrane depolarisation →Ca2+ influx →insulin secretion

321
Q

structure of Katp channel and make up in beta-cells

A

octomeric.

4 Kir6.2 and 4 SUR1 in beta-cell (Kir6.1 elsewhere in body)

322
Q

what does an inc ATP/ADP ratio cause in Beta-cell?

A

closure of Katp → will depolarise cell (as K+ efflux no longer constant negative cell change becomes more neutral)

323
Q

where does ATP and ADP-mg2+ bind to in Katp? what does each do?

A

ATP binds to Kir6.2 → closure →depolarsing →inc insulin

ADP-mg2+ binds to SUR1 →keeps opened →maintains resting potential →reduce insulin

324
Q

how do SUs work?

A

bind to SUR1 subunit and act to close the channel (displace ADP-Mg2+ binding on SUR1) → inc insulin

325
Q

why are SU’s MOA insulin dependant?

A

because need Beta-cells to act on SUR1 channel.

called insulin secretatogues

326
Q

examples of first generation SU and second gen?

A

are tolbutamide (first generation),

glibenclamide, gliclazide (commonest) and glipizide (second generation)

327
Q

SU’s become less effective as time goes on? why?

A

as t2DM disease process occurs, more B-cells are lost so less of an effect it has.

328
Q

SU side effects

A

Hypo (as act independent of BG conc).

undesirable weight gain

329
Q

why do SU’s cause weight gain?

A

as insulin is anabolic, inc appetite and reduces loss of glucose in urine

330
Q

what makes certain patients on SU at greater risk of a hypo?

A

greater risk with long-acting agents, elderly or paint with reduced hepatic/kidney clearance (esp CKD)

(eliminated by kidney so as kidney function falls harder to clear - also long-acting harder to reverse effects than short acting -tolbutamide)

331
Q

when are SU’s used?

A

1st line - if intolerant to metformin, or with weight loss.(low BMI)

2nd line - as backup to metformin (+TZD’s)

332
Q

when should SU’s be avoided?

A

CKD, elderly (>65), pregnant

333
Q

Glinides (Meglitinides)MOA

A

Act similarly to the sulfonylureas – bind to SUR1 (at a distinct benzamido site) to close the KATP channel and trigger insulin release

(AFFECTED BY BG conc)

334
Q

example of Glinides (Meglitinides)?

A

repaglinide, nateglinide

335
Q

why are repaglinide and nateglinide sometimes superior to SU’s?

A

less chance of hypo (as BG correlation)

safer in CKD (as eliminated by liver)

rapid onset of action (<1hr)

336
Q

why should Glinides (repaglinide and nateglinide) not be used?

A

sever hepatic impairment

pregnancy/breastfeeding

337
Q

DPP-4 Inhibitors (Gliptins) MOA

A

actions of GLP-1 and GIP very rapidly terminated (within minutes) by the enzyme dipeptidyl peptidase-4 (DPP-4)- inhibits endogenous insulin; DPP-4 inhibitor prolongs actions. (incretin effect).

therefore only works if B cells numbers are okay

338
Q

what happens to the incretin effect in type 2DM

A

it is reduced.

339
Q

example of DPP-4i? pros and cons?

A

Sitagliptin.

no hypo, neutral weight

nausea , not very potent

340
Q

give 2 examples of incretin analogues

A

extenatide, liraglutide.

341
Q

how do incretin analogues work?

A

miming the action of GLP-1 (agonists)

(but are long lasting).

342
Q

pros of incretin analogues

A

Increases insulin secretion/suppresses glucagon secretion

slows gastric emptying

decreases appetite

weight loss

reduced hepatic fat accumulation

343
Q

cons of incretin analogues

A

injection (SC) - either weekly or once/twice daily.

nausea, hypo and [rarely] pancreatitis

344
Q

example of an alpha-Glucosidase Inhibitors

A

Acarbose

345
Q

how do alpha-Glucosidase Inhibitors work?

A

inhibits alpha-glucosidase (brush border enzyme in gut that breaks down big CHO into glucose)

This causes delayed absorption of glucose thus reducing post-prandial inc in BG

346
Q

when are alpha-glucosidase inhibitors used?

A

very rarely (life T2DM not controlled by lifestyle and other drugs)

far-east countries use them more

347
Q

con’s/adverse effects of alpha-glucosidase inhibitors?

A

GI: sugar passed into bowls where bacteria metabolise causing inflammation and gases (flatulence, loose stools, diarrhoea, abdominal pain, bloating)

not very effective

348
Q

pros of alpha-glucosidase inhibitors?

A

no risk of hypo

349
Q

Biguanides/metformin MOA (4 things)

A

Reduces hepatic gluoconeogenesis [by stimulating AMP-activated protein kinase (AMPK)]

Incr glucose uptake and utilization by skeletal muscle (increases insulin signalling)

reduced CHO absorption

inc fatty acid oxidation

350
Q

when is metformin used?

A

First line agent in the treatment of T2DM in obese patients (with normal hepatic and renal function)

351
Q

pro’s of metformin

A

prevents hyper but does NOT cause hypo.

weight loss (as does not promote insulin release)

oral, easily combine with others

352
Q

con’s of metformin

A

GI common and intoleraable for some (diarrhoea, nausea, anorexia)

[rarely] lactic acidosis - avoid in patient with renal/hepatic disease.

353
Q

TZD’s/glitazones MOA

A

ENHANCE THE ACTION OF INSULIN AT TARGET TISSUES, but do not directly affect insulin secretion [reduce the amount of insulin required to maintain a given blood level of glucose]

act as agonists of PPAR-gamma which associated with RXR. - modified transcription factors promoting genes encoding several protiens involved in insulin signallng

354
Q

example of TZD?

A

pioglitazone (others removed as hepatotoxic/anti-CVS).

355
Q

pro’s of TZD/glitazone?

A

Promote fatty acid uptake and storage in adipocytes, rather than skeletal muscle and liver

Reduced hepatic glucose output

356
Q

cons of TZD/glitazone?

A

weight gain

fluid retention (inc HF risk) - not given to pre-existing HF patients

inc bone # risk

not given in those with liver disease - hepatotoxic

357
Q

SGLT2 MOA

A

not dependent upon insulin

to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria

358
Q

SGLT2 pro’s

A

No hypo

calorific loss (weight loss)

renal protection

CVS benefit

359
Q

SGLT2 cons

A

Thrust/UTI

Endocrinology (7 decks)

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