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Delta Med - Endocrinology > Endocrinology 2 - Diabetes and obesity > Flashcards

Endocrinology 2 - Diabetes and obesity Flashcards

1
Q

What is the RR of cancer in pts with BMI >40?

A

RR 1.5 in men, 1.6 in women.

37% increase in oesophageal cancer (reflux)
others increased - Colon, breast, renal, endometrial, gallbladder

Physical activity has a 40% reduction in bowel ca and a 30% reduction in postmenopausal breast cancer

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2
Q

What effect does central adiposity have on hormones?

A 
Increased:
Visfatin
Resistin
Leptin
FGF 21
RBP-4
Cortisol

Reduced:
Adiponectin

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3
Q

What cytokines are increased by visceral adipose tissue?

A 
TNF-alpha
IL-1B
IL-6
PAI-1
MCP-1
hsCRP
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4
Q

What are mutations causing obesity in humans?

A

Ob - AR - leptin deficient
ObR - AR - defective leptin signalling
POMC - AR - reduced production of POMC-derived ligands
Prohormone Convertase 1 - Recessive - Defective post-translational processing of POMC to MSH
MC4-R - dominant - impaired function of the MC4-R

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5
Q

What is the role of leptin?

A

Peptide hormone, synthesized in adipocytes in proportion to cell size.
Inhibits food intake and increases energy expenditure.
Reduces expression of NT that increase food intake (NPY, AgRP)
rare cases of leptin deficiency in humans lead to insatiable appetite and obesity - normalises with Rx

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6
Q

Where is the leptin receptor found?

A

found in the choroid plexus
crosses BBB via saturable mechanism
most obese people are leptin resistant - high leptin levels with saturated BBB transport.
Central insensitivity - acute infusion decreases appetite via NPY suppression in the hypothalamus.
High fat diet attenuates leptin effects before increase in body fat.

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7
Q

What are hypothalamic triggers of satiety and hunger?

A

Neuropeptide Y (NPY) and Agouti-related peptide (AgRP) increase hunger

aMSH and CART both reduce hunger

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8
Q

What are gut hormones that decrease hunger?

A

CCK
GLP-1
Oxyntomodulin
PYY3-36

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9
Q

What are pancreatic enzymes that inhibit hunger?

A

Amylin
Insulin
Pancreatic peptide

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10
Q

What are fat enzymes that inhibit hunger?

A

Leptin
Adiponectin
Insulin

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11
Q

What are stomach enzymes that increase hunger?

A

Ghrelin ONLY

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12
Q

Which bariatric surgeries can cause malabsorptive states?

A

Roux-en-Y

Biliopancreatic diversion without duodenal switch

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13
Q

What bariatric surgeries influence satiety hormones?

A

Sleeve gastrectomy (reduced ghrelin)
Roux-en-y
Biliopancreatic diversion without duodenal swithc

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14
Q

What are the only interventions that lead to sustained weight loss >2 years?

A

Gastric bypass and lap banding

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15
Q

What long term advantages to gastric bypass procedures provide over LAGB?

A

weight loss
T2DM control/remission
Hypertension
dyslipidaemia

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16
Q

What weight loss is expected in combination phentermine+topiramate treatment of obesity?

A

8.1kg vs 1.2kg in placebo arm.
teratogenic
side effects driven by topiramate - depression, peripheral paraesthesias, dizziness

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17
Q

How is DM diagnosed?

A

DM:
FBG >=7.0 OR RBG>=11.0% OR 2hr OGTT >=11.1% OR HbA1c >=6.5%

IFG: 6.1-6.9 FBG on 2hr OGTT (2hr =7.8 on 2hr OGTT

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18
Q

What is the relative risk reduction of diabetes in metformin use and lifestyle modification?

A

Metformin 31%

Lifestyle 58%

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19
Q

What proportion of B-cell function is lost prior to diagnosis of T2DM?

A

50%

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20
Q

What insulin response is first lost in DM?

A

first phase insulin response, prior to eating meal in both type 1 and type 2

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21
Q

What is the MoA and function of insulin?

A

binds to insulin receptors on cells.
Via IRS-1/IRS-2, causes cell growth and differentiation via MAP kinase, lipid synthesis via PI-3 kinase and aPKC and protein metabolism via Akt and upreguliation of GLUT-4, increasing glucose uptake

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22
Q

What is the ominous octet in T2DM?

A 
Decreased insulin secretion
decresed incretin effect
increased lipolysis
increased glucose reabsorption
decreased peripheral glucose uptake
neurotransmitter dysfunction
increased hepatic glucose production
increased glucagon secretion
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23
Q

What is the MoA of GLP-1 in humans?

A

on food ingestion, GLP-1 is released from the L cells in the jejunum and ilieum
Stimulates insulin secretion, suppresses glucagon secretion, slows gastric emptying, improves insulin sensitivity, reduces food intake

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24
Q

Where is GIP released and it’s location of action?

A

Released from K-cells, acts upon pancreatic beta cells to increased insulin production.

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25
Q

What is the mode of action of exenetide?

A

GLP-1 receptor agonist - 50% homology with human GLP-1
subcut injection BD
causes 1.6kg wt loss at 12 weeks, 5.3kg at 3 years.
SEs: nausea, vomiting and diarrhoea
possible risk of acute pancreatitis, possibly 2 fold.

26
Q

What is the mode of action of liraglutide?

A

GLP-1 analogue, 97% homology with human GLP-1
long acting, once daily injection.
At least as effective as exenetide
better tolerated, similar SE profile
Concerns re thyroid c-cell cancer in mice

27
Q

What is the mechanism of action of sitagliptin (other -gliptins)?

A

DPP-4 inhibitors - increase endogenous incretin levels
lower HbA1c by 0.5-1.0%
weight neutral.
No increase in CV events, but no benefit either
SEs: sinusitis/URTIs, headache, allergy, nausea, diarrhoea
? heart failure
? pancreatitis
Not recommended in renal failure - linagliptin does not require dose adjustment

28
Q

What is the site and function of SGLT-2?

A

Located in S1, proximal tubule, reabsorbs 90% of glucose. SGLT-1 proximal straight tubule 10% of glucose

29
Q

What is the mechanism of action of -gliflozins?

A

Block SGLT-2 and increase renal excretion of gluclose

30
Q

What effect does dapagliflozin have on weight and HbA1c?

A

decreased HbA1c by 0.8% vs placebo 0.3%, and decreases weight by 2.9% vs placebo 0.9%.

31
Q

What are AEs and CIs of the gliflozins?

A

renal impairment, severe hepatic disease - C/I
interacts with loop diurectics
Increased risk of UTIS, genital infections, orthostatic hypotension, volume depletion, hypoglycaemia with SU/insulin

32
Q

What is the mechanism of action of gliclazide?

A

bind to K+ ATP sensitive channels on B-cells, causing depolarisation via Calcium channels and increased insulin secretion.

AEs include severe hypoglycaemia and weight gain.

33
Q

What is the mechanism of action of glitazones?

A

Glitazones = pioglitazone and rosiglitazone
bind to PPAR-gamma ain increase transcription of insulin, increasing peripheral insulin resistance. modest reduction in BP, increased HDL and decreased TGs

AEs: fluid retention, increased risk of exacerbation of CCF, weight garin and increased risk of fractures. May be associated with bladder CA, monitor liver transaminsases carefully. risk of hypoglycaemia with insulin.

34
Q

What is the strongest predictor of CV death in patients with DM?

A

albuminuria

35
Q

What does a 1% reduction in HbA1c achieve?

A

37% reduction in microvascular complications
21% reduction in diabetes related deaths
21% reduction in any diabetes related endpoint
14% reduction in myocardial infarction

36
Q

What effect does metformin have on MI rates compared to conventional therapy in obese patients with T2DM

A

39% reduction in myocardial infarction

37
Q

What is the outcome regarding mortality in meta-analyses of UKPDS, ADVANCE, ACCORD studies comparing standard to intensive glucose control?

A

No significant reduction in mortality from all cause or cardiovascular causes.

38
Q

Which patients in the ACCORd study were shown to have a benefit with regard to CV events on a sub-group analysis?

A

Those without a previous CV event and those with a HbA1c

39
Q

What endpoints had significant reductions in long term follow-up in the ACCORD study?

A

Any DM endpoint
Microvascular disease
Myocardial Infarction
All cause mortality

40
Q

What is the outcome of a long-term metaanalysis of diabetes studies wrt CV events and all cause mortality in intenstive treatment?

A

Signifcant reduction in CV events however no significant difference in all cause mortality.

41
Q

What was the outcome of the EMPA-REG trial?

A

Empagliflozin was shown to have a significant reduction in 3 point mace (death, nonfatal MI, non-fatal stroke), death from CV causes, death from any causes and hospitalisation for heart failure

Also reductions in weight, HbA1c

42
Q

What percentage of patients met intensive treatment targets in the Steno-2 Study?

A

Significant difference in targets reached in cholesterol and systolic blood pressure only.

43
Q

What was the outcome of the steno-2 study (multifactorial intervention in T2DM)

A

53% RRR in cardiovascular death and complications, improvement in rates of nephropathy, retinopathy and autonomic neuropathy, but not peripheral neuropathy.

44
Q

What is the risk in identical twins of developing T1DM, 1st degree relatives?

A

50%, 10-15%

16% in HLA identical sibling

45
Q

What HLA genes are associated with T1DM?

A

HLADR3,4 and DQ2,8 are associated with t1dm and account for 50% of the risk.

46
Q

What other diseases are associated with HLADR3,4 and HLADQ2,8?

A

Autoimmune thyroid disease (1 in 5)
Coeliac disease (1 in 12)
Pernicious anaemia

Addison’s disease, RA, AI hepatitis, vitiligo, ITP

47
Q

What antibodies are detected in early T1DM?

A

anti-insulin
anti-GAD (72% Sn, 99.3% Sp)
anti-IA-2 (99.5% Sp)
ZnT8

48
Q

What are proposed environmental risk factors for T1DM?

A 
maternal age >25, preeclampsia, neonatal respiratory disease, jaundice, esp ABO incompatibility
enterovirus infection
vit d deficiency
early gluten exposure
adiposity - insulin resistance
49
Q

What infiltrate is seen in T1DM?

A

early - CD8 T cells, macrophages, CD4 t cells

late - CD8 T cells, CD20 B-cells, macrophages

50
Q

What effect did intensive glucose management have on HbA1c in the DCCT study?

A

1.9% reduction in intenstive group

51
Q

What was the reduction in retinopathy/nephropathy in the DCCT trial?

A

primary prevention group - 75% reduction in intensive cohort
secondary intervention group - 50% reduction (retinopathy)

34 and 43% reduction in nephropathy

shown to have extended benefit wrt nephropathy post study completion in EDIC study also signifcant reduction in macroalbuminuria despite HbA1c equilibrating post completion of active study treatment.

52
Q

What was the outcome of DCCT with regard to neuropathy?

A

60% reduction in clinical neuropathy?

53
Q

What -opathy has the greatest reduction in risk with reduction in HbA1c in T1DM?

A

retinomathy > nephropathy > neuropathy > microalbuminuria

54
Q

Which patients are not for intensive hypoglycaemic control per DCCT study?

A

patients with recurrent hypoglycaemia
patients with macrovascular complications
young children

55
Q

What did the EDIC study show wrt to long term CV risk in intensive Glycaemic control?

A

Significant reduction in CV events in intensive treatment arm, even after the study was completed.

56
Q

What are clinical benefits of CSII pumps?

A

reduction in HbA1c by 0.3%
reduced severe hypoglycaemia
improved QoL
Observational evidence of 42% reduction in CV mortality and 27% reduction in all cause mortality.

57
Q

What are outcomes of islet cell transplantation?

A

insulin independence
reduce insulin requirement/frequency
improved HbA1c and less hypoglycaemia

indicated in patients with severe hypoglycaemia with unawareness and no significant chronic complications.

58
Q

What are Dx criteria for LADA?

A

Age 30-75
ADA criteria for DM met
Evidence of GAD Ab >5units
Period of insulin independence - diet/oral antidiabetic therapy

59
Q

what proportion of age >25yrs are positive for islet antibodies?

A

10%

60
Q

What are 5 distinguishing clinical features of LADA?

A

age

Delta Med - Endocrinology (4 decks)

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