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Medsci 312 > Lecture 25; Type Two Diabetes > Flashcards

Lecture 25; Type Two Diabetes Flashcards

1
Q

What sort of disease is type 2 diabetes?

A

Type 2 diabetes is a progressive disease in which glucose tolerance slowly degenerates over a number of years and mainly affects older people

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2
Q

What are the levels of circulating insulin when T2D is diagnosed?

A

At diagnosis patients have normal or excessive circulating levels of insulin implying that the pancreas has not been completely destroyed

As the disease progresses they end up with no insulin.

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3
Q

What can happen to insulin levels in T2D?

A

As the disease progresses the beta-cells lose the ability to secrete insulin and/or die.

In severe insulin resistance this is associated with an accumulation of amyloid plaques in the beta cells and in some patients this may contribute to the death of beta cells and thus the development of diabetes.

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4
Q

What can distinguish type two from type one diabetes?

A

Circulating levels of insulin distinguish Type-2 from Type 1 diabetes and importantly most type-2’s do not have islet cell antibodies at diagnosis implying any destruction of pancreas is by non immune mechanisms

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5
Q

What are the characteristics of type two diabetes?

vs

Type one;

A
  • Late age onset (50-60)
  • Insulin at diagnosis (but insulin resistance therefore can enhance existing insulin effects with drugs
  • Linked to lifestyle factors; Inc Food, Obesity (intrinsically linked), decreased activity, increased warmth

type one

  • Early age onset (youth)
  • No insulin
  • Antbodies against beta cell proteins
  • Genetic
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6
Q

What is enhancing the prevalence of type two diabetes?

A

The interaction between environment and genetic predisposition

Environment;

  • Warmer lifestyle (majority of energy spent keeping warm usually, therefore less thermogenesis)
  • Less physically active
  • Readily available energy dense foods

Note* People are usually pretty good at maintaining a constant body weight

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7
Q

Describe the burden of type two diabetes in new zealdn;

A
  • 257,000 diagnosed and a estimated further 100,000 undiagnosed
  • Reduced lifespan as causes many diseases primarily CV ones.
  • Reduces productivity and quality of life costing the government billions.
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8
Q

Describe the differences in type two diabetes prevalence and ethnicitity;

A

Among the 60-70 year olds;

  • Pasifika and indoasians ~40%
  • Moari ~30%
  • Europeans ~15%`
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9
Q

Does increased risk for type two diabetes reflect reality?

A

Risk does not mean that the individual will get type two diabetes

Only 40% of obese people have it and 5% of people with healthy BMIs 22 have it.

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10
Q

Whats important to note for % body fat and BMI?

A

At a uniform BMI

  • Asians will have a higher % body fat (intrabdominal)
  • Pacific islanders will have more muscle and less fat
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11
Q

How does a person spend most of their energy?

A

Basal metabolic rate.

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12
Q

Describe what factors can lead to type two diabetes in obesity;

A

Excessive nutrition / obesity =

  • Insulin resistance
  • Increased metabolic load
  • Systemic inflammation

via genetic susceptibility

Islet response to this;

  • Inflammation stress
  • ER stress
  • Metabolic/oxidative stress
  • Amyloid stress
  • Stressed islet integrity

= decreased beta cell function and mass leading to type two diabetes

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13
Q

What is a unique factor being explored that may cause type two diabetes?

A
  • Changes in the microbiome
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14
Q

How may changes in the microbiome lead to T2D?

A

Microbiome produces short chain FAs and other metabolites.

Influences body metabolism

Experimentally;
Transferred the microbiome of a skinny mouse to an obese mouse and it lost weight by decreasing food consumption

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15
Q

To what degree may genetics cause type two diabetes?

A

Genetics have a 40-70% influence in obesity and type two diabetes.

  • Identical twins studies back this
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16
Q

Therefore what is likely to influence insulin function?

A

A combination of environment and genetic interactions.

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17
Q

What is the first step in the development of type two diabetes?

A

Initial triggers for diabetes leads to insulin resistance.

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18
Q

What is insulin resistance?

A

Insulin resistance

  • Reduced ability for insulin to work on its receptors in the fat, liver and muscles
  • Therefore cannot regulate glucose metabolism via these signalling pathways.
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19
Q

What is the initial response to insulin resistance?

A

Body compensates by making more insulin and thus blood glucose is normal.

20
Q

How does insulin resistance continue to develop?

A

Over time the insulin resistance gets worse and the beta cells arent able to produce sufficient insulin, blood glucose rises and the clinical features of type two diabetes appear.

Diabetes is diagnosed because of the high levels of blood glucose.

21
Q

When does prediabetes occur?

A

When you have insulin resistance but the body is able to cope by producing more insulin

Higher levels of insulin are not toxic and beta cells have some reserve capacity.

22
Q

What are the causes of insulin resistance?

A
  • Factors circulating in the blood (blood lipids)
  • Obesity (fat cells get full) = (steatosis)
  • low grade chronic inflammation
  • High levels of anti-insulin acting hormones
  • Genetics
23
Q

What are the type two diabetes symtpoms?

A

Pretty much the same as type one except this is when insulin resistance has become sufficiently bad

i.e neuropathy, retinopathy. etc.

24
Q

Describe te inflammation theory of insulin resistance;

A

Excess lipid deposition in adipocytes and ultimately in liver results in recruitment of inflammatory immune cells which results in increased release of inflammatory cytokines and lipids that cause insulin resistance in multiple tissue

  • Macrophages can be recruited and enhance this effect.
25
Q

What inflammatory markers are released by excess lipid deposition?

A
  • Reduced leptin (regulates apetite)
  • ## Reduced Adiponectin (promotes insulin sensitivity)
  • IL6, TNFa, FAs, Resistin all induce insulin resistance in the liver, muscle and adipose.
26
Q

What are some hormones that can cause insulin resistance?

A
  • Steroids
  • GH
  • Adrenalin (stress hormone, cAMP induced glycogen phosphorylase and gluconeogenesis)
  • Glucagon

11b HSD2 is present in adipose to prevent cortisol aciton, but cortisone enhances insulin resistance anyways

27
Q

How do factors circulating in the blood contribute to insulin resistance?

A

FAs, lipids in circulation cause problems in the muscles, adipose, liver and reduce insulin signalling

28
Q

How does steatosis contribute to insulin resistance?

A

When adipocytes are overloaded they can’t store more lipid so it spills over and is stored ectopically in other tissues, particularly in liver where it results in liver insulin resistance and Non Alcoholic Fatty Liver Disease. Now liver is not responding to insulin well.

29
Q

Whats an instance where people dont have fat stores at all and why is this bad?

A

Lipid dystrophy, bad because it immediately leads to steatosis. (NAFAD)

30
Q

List the treatments a type two diabetes would go on in NZ?

A

First; Metformin (increases insulin sensitivty)
- Once max dose is reached (as resistance progresses)
Then; Sulfonylureas (increase insulin secretion by blocking K channels)
- Once all beta cells are destroyed
then;
Injectable insulin.

Progressive disease

31
Q

Write some notes on metformin

A

(biguanides is the actually chemical)
- Oral
- Cheap
Acts on the liver by increasing AMP Kinase activity and thus improved liver insulin sensitivity.

32
Q

Write notes on sulfonylureas;

A
  • Oral
  • Cheap
  • Block ATP sensitive K channels in beta cells thus increased RMP and insulin release.

BUT

  • Can lead to hypoglycemia if food is not consumed
  • Doesnt work if the beta cells cant produce insulin

Note* these only slow the disease

33
Q

What are some drugs used overseas?

A

Modulate GLP1 activity (receptor agonists, DPP4 inhibitors)
Thiazloiidnediones
SGLT2 inhibitors
Pramlintide

34
Q

How do drugs modulating the GLP1 system work?

A

GLP1 agonists = increased activity (injection)
DPP4 inhibitors increasing plasma GLP1 (oral, better)

GLP1 promotes B1 survival, mass, regulates appetite (thus people tend to lose weight on these drugs), enhances insulin secretion and inhibits glucagon

35
Q

How do Thiazloiidnediones work?

A
  • Targets PPARg
  • Reduces inflammation and insulin resistance
    BUT
  • Increases adipocytes

Some CV side effects

36
Q

What are the advantages of SGLT2 inhibitors?

A

Lowers HBA1c levels by about 1% so a significant effect

Lowers blood glucose without raising insulin so can work in pre-diabetes right through to full blown diabetes

Also means it can have additive effects with other types of antidiabetic drugs.

An additional benefit is that it also reduces sodium re-uptake and so there is a beneficial effect on blood pressure.

37
Q

What are the downsides to SGLT2 inhibitors?

A

Increased risk of urinary tract infections

Some indication of increased risk of cancer but this is not yet confirmed

38
Q

What is by far the most effective cure for T2D?

A

Gastric bypass surgery

80% have no T2D in the 20 year follow up study

Instant cure. Not permanent though

39
Q

How does gastric bypass surgery work?

A

Results in improved insulin action (i.e less insulin resistance) and improved release of gut hormones in response to food intake e.g GLP/GIP.

The effects of the surgery are which is in part due to weight loss, in part due to less sugar intake because of smaller meal sizes

The bariatric surgery can greatly reduce severity of Type-2 diabetes and prevent the development of diabetes in people who are in pre-diabetic stage.

40
Q

Does lifestyle intervention work?

A

NO

Prescribed exercise and diet even when maintained does not stop type two diabetes and often individuals cannot maintain this regime for years

41
Q

What sort of signalling is decreased in diabetes?

A

Type-2 diabetes and obesity are associated with reductions in levels of melatonin signalling and decreased levels of melatonin signalling are associated with impairments of glucose metabolism. Studies ongoing looking at whether melatonin supplementation may be useful in some type-2 diabetics.

Therefore looking at agonists for MC4R to treat

42
Q

How is genetics linked to T2D?

A

Polygenetic!

Therefore Candidate gene approached revealed nothing

thus GWAS (common SNPs)

43
Q

What is a SNP that is abundantly common?

A

For example - TCF7L2 as the most prominent polygenic factor (the Odds Ratio for this is about 1.4) and this was found in many populations around the world. This is a protein involved in Wnt/-catenin pathway, how it causes diabetes still not well understood but TCF7L2 is important in regulating beta-cell function.

44
Q

What is further shown regarding SNPs?

A

There are many common variations in genes that predispose populations to T2D but there is also many rare variants too.

45
Q

How does the number of SNP mutations relate to T2D?

A

The SNPs in GWAS are common so one theory is that the more disease associated SNPs there are the more risk a person has of getting type-2 diabetes although this is difficult to definitively prove

Additive effects

46
Q

Whats a SNP close to home?

A

Moari and pacifica have CREBRF variants

One variant = 1.5BMI increase (huge)

But odds ratio for T2D is 0.6 (decreased risk) but increased BMI

Medsci 312 (28 decks)

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