Diabetes Type 2 Flashcards
(89 cards)
1
Q
What is type 2 diabetes?
A
A disease resulting in the malfunction of insulin at target cells (causing hyperglycemia)
2
Q
How does t2 diabetes differ from t1?
A
t2 = insulin-independent DM
3
Q
Roughly how many cases of diabetes are solely t2?
A
90%
4
Q
How long does it take for T2 diabetes to develop?
A
Can take years to develop as a result of changing environment
5
Q
What are the 2 hall marks of diabetes t2?
A
- Insulin resistance
- Compromised B-cell function
6
Q
What does insulin resistance lead to?
A
Impaired ability of insulin to 1. promote peripheral glucose uptake as well as
2. suppress glucose output by the liver
7
Q
What does compromised B-cell function lead to?
A
Insufficient insulin secretion to combat insulin resistance; occurs later in disease progression
8
Q
What are 3 stages involved in developing type 2 diabetes?
A
- Normal glucose tolerance (NGT) = fasting plasma glucose is within normal range, insulin levels rise due to B-cell compensation.
- Pre-diabetes/Impaired glucose tolerance [IGT] and impaired fasting glucose [IFG] = Fasting plasma glucose or post-OGTT levels are elevated, resulting in hyperinsulinemia (B-cell compensation)
- Overt type 2 diabetes = fasting plasma glucose is elevated and insulin levels are low (B-cell dysfunction)
9
Q
What happens when insulin is unable to exert its effect as efficiently?
A
Pancreatic beta cells compensate by producing excess insulin so as to combat high blood glucose levels
10
Q
What precedes and predicts type 2 diabetes?
A
Insulin resistance
11
Q
What happens to glucose metabolism as type 2 diabetes progresses?
A
Becomes more impaired
12
Q
For a diabetic individual, what is the expected result of an oral glucose tolerance test (OGTT)?
A
Impaired glucose tolerence
13
Q
What is hyperinsulinemia?
A
When beta cell compensation is occurring, but insulin cannot exert its metabolic effect (even in high amounts)
14
Q
What does beta cell compensation progress to?
A
Beta cell dysfunction (loss of beta cells like t1 diabetes)
15
Q
What does this graph depict?
A
- depicts changes in insulin secretion AND glucose uptake in the tissues as a function of insulin sensitivity within the measure of insulin resistance during the three phases of type 2 diabetes pathogenesis
- If we look further type 2 diabetes starts to progress
–> hyperinsulinemia and gradual decrease in
insulin levels = accompanied by a further decrease in insulin sensitivity - Insulin response depicted highlights beta cell changes first 2 phases:
1. elevation of line in graph 1 represents beta cell compensation
2. the negative slope in graph 2 represents beta cell dysfunction
16
Q
What does the top part of this graph show?
A
Shows plasma insulin levels in response to an OGTT
= means it’s the beta cell function in response to glucose
17
Q
What is this graph depicting?
A
Shows the described glucose uptake into tissues OR the insulin sensitivity measured by a euglycemic clamp
= There is a gradual decrease in insulin sensitivity which is accompanied by the rising insulin levels in
the first normal glucose tolerance as well as impaired tolerance phase
= Insulin levels = rising quite high in the impaired glucose tolerance phase and insulin sensitivity =
dropping further
18
Q
What is the euglycemia clamp?
A
technique to measure in vivo insulin sensitivity during an OGTT
19
Q
Risk factors tend to occur in clusters, and the more risk factors one has the more likely one will develop T2 diabetes. Some factors are fixed and some are a result of lifestyle.
a) What are fixed factors?
b) What are environmental factors?
A
a) Fixed factors = not modifiable (age, gender, genetic background, ethnicity and low birth weight)
b) Environmental/Lifestyle factors = modifiable (obesity, diet, decreased sleep, elevated consumption of sugar)
20
Q
Explain how genetic factors contribute to SOME risk of TD2.
A
- Heritability accounts for about 40-80% of disease onset
- Polygenic disorder – no single gene explains disease susceptibility (multiple
gene defects may contribute to susceptibility) - Several gene polymorphisms implicated – often genes controlling insulin secretion & action, β-cell proliferation and various metabolic genes
21
Q
Explain how obesity is a core, modifiable risk factor.
A
- Obesity is the main modifiable risk
factor for type 2 diabetes - Accounts for 80-85% of
overall risk of developing type 2 diabetes - Small amounts of weight loss (5 –10%) can prevent/delay the
development of type 2 diabetes in high-risk individuals - Weight loss in type 2 diabetic patients has shown improved glucose homeostasis
- Map shows global prevalence of obesity among adults
More intense red = US, Europe and SA
22
Q
What is DALY, and how does the burden of disease contribute to weight gain?
A
DALY = disability-adjusted life year –> the number of years lost in life due to ill health, disability or death.
23
Q
How do we balance our energy needs and requirements to control our body weight?
A
- Neutral energy balance:
* Intake = expenditure
* Constant body weight - Negative energy balance:
* intake < expenditure
* Lowers body weight - Positive energy balance:
* Intake > expenditure
* Weight gain/obesity
24
Q
What happens when people who diet plateau after initial weight loss?
A
Small compensatory/homeostatic mechanisms in metabolism may occur to maintain a new level of energy balance
25
Where is the "satiety" centre found in the brain?
In the hypothalamus, specifically the arcuate nucleus
26
Which 2 important signalling factors play a central role in satiety?
1. Neuropeptide Y (NPY) = potent appetite stimulating hormone that activates hunger, food intake and weight gain in the long run.
2. Melanocortins = suppress appetite and food intake, leading to weight loss.
27
What are the roles of leptin and insulin in satiety signalling?
* Satiety signaling is initiated during the consumption of a meal.
* The rise in blood glucose and nutrients trigger insulin release from pancreatic β-cells that in turn, among other functions, stimulates the release of the adipokine leptin from adipocytes.
* Both leptin and insulin bind to their respective receptors within the arcuate nucleus and initiate downstream effects.
* Both hormones act to inhibit NPY-secreting neurons (indicated by the red arrows) INHIBITORY EFFECT
* leptin simultaneously also stimulates pro-opiomelanocortin (POMC)-secreting neurons (indicated by the green arrows) STIMULATORY EFFECT
28
What are the downstream effects of insulin and leptin in the satiety centre?
1. NPY secretion and concentrations are decreased by the inhibitory effects of insulin and leptin (dotted arrows mean reduced effect; solid arrows mean increased effect)
2. The leptin stimulation of POMC-secreting neurons result in elevated levels of melanocortins released from these neurons
3. From the previous slide, we know that NPY and melanocortins have opposing effects on appetite, but we still need to fill in some details:
* NPY would normally activate lateral hypothalamic area (LHA) neurons and inhibit paraventricular nucleus (PVN) neurons, while melanocortins would have the exact opposite effect
* The LHA neurons normally release orexins that usually stimulates appetite and food intake
The PVN neurons normally release corticotropic-releasing hormone that has an appetite inhibiting effect
* Due to the actions of leptin and insulin (remember it is during food consumption), the resulting combination of downstream effects is overall inhibition of LHA neurons and decreased orexins, combined with overall activation of PVN neurons and elevated corticotropic releasing hormone levels
* This combination suppresses appetite and food consumption in this setting
29
What are the short term regulatory effects of food intake? (ghrelin and PYY3-36)
Please remember the finer details – where each hormone/factor is secreted from and under what conditions, what does it act upon and how, etc.
* The short-term/daily regulators of food intake are the counter-regulatory hormones ghrelin and peptide YY3-36 (PYY3-36).
* Both hormones act on the NPY-secreting neurons, however, with opposing effects.
* Ghrelin would be released from the stomach before meal consumption (i.e. in a hunger state) and stimulate NPY-secreting neurons to release NPY, with the downstream effects of stimulating the LHA neurons and inhibiting the PVN neurons, with higher orexins levels and lower corticotropic releasing hormone levels.
* Together, this stimulates appetite and food intake.
* PYY3-36 is released from the intestines when a meal is being consumed, and acts in a reciprocal manner to ghrelin.
30
Why is leptin found in high concentrations in obese people?
* Obese people tend to have higher amounts of adipose tissue
* Adipokines = hormones and cytokines specifically secreted from adipocytes
* So, leptin levels are higher in overweight and obese individuals
MORE adipose tissue = MORE adipokines = MORE leptin
31
If leptin suppresses appetite and would hence result in decreased food intake and weight loss, why do some obese individuals have high circulation leptin levels (i.e. hyperleptinemia)?
These people are believed to have developed leptin resistance (similar to insulin resistance)
32
What is leptin resistance?
* It is thought that these individuals have a “reset” homeostatic control, where higher levels of leptin are required to achieve the stimulatory effect seen in normal weight individuals
* The increased adipose stores in overweight/obese individuals may also contribute to higher leptin output (greater source)
* Together with defects in leptin receptor binding, this results in defective leptin signaling
* Hyperphagia (overeating) is common in this case, e.g. in individuals with leptin or leptin receptor genetic defects
33
Explain what is observed in the db/db, ob/ob and wild type murine models.
1. The db/db mouse model is a leptin receptor knockout model that contains a mutation in the leptin receptor gene --> downregulation of leptin receptor expression/fewer receptors available
2. The ob/ob model is a leptin deficient mouse strain with a mutation in the gene for leptin --> complete deficiency of leptin
34
What do both murine models, db/db and ob/ob have in common, compared to the wild type?
Both models develop
* hyperphagia,
* obesity,
* hyperglycemia,
* hyperinsulinemia and
* insulin resistance
compared to wild type controls that remain lean
35
Name 5 possible mechanisms of leptin resistance and hyperleptinemia
1. Self-regulated
2. Cellular regulators
3. Circulating regulators
4. Limited tissue access
5. Genetic variations
36
Explain the self-regulated mechanism of leptin resistance
= negative feedback
37
Explain the cellular regulator mechanism of leptin resistance
= signalling intermediates regulate the effects of leptin
38
Explain the circulating regulators mechanism of leptin resistance
= SLPs bind to leptin, but in certain cases the binding proteins are overactive --> thus bind leptin to a greater degree and decreasing leptin action
39
What are some causes of obesity?
1. Genetics – e.g., FTO gene disturbances
* 1 faulty allele = increases obesity risk by 30%
* 2 faulty alleles = increase obesity risk by 70%
2. Metabolism: Individual variation in energy extraction from ingested nutrients (some individuals digest and extract nutrients more efficiently)
3. Composition of gut microbiome – digestion
4. Psychosocial effects affecting eating habits and influence nutrient intake: portion size, personal preference of food types, availability and accessibility to nutritious food, eating disorders, high fat cell mass and number, lack of exercise
40
What are the downstream effects of defective insulin secretion on the brain, liver, muscle and adipocytes?
Brain = increase in food intake --> insulin resistance
Liver = increase in glucose production --> increase in plasma glucose
Muscle = decrease in glucose uptake --> increase in plasma glucose
Adipocytes = increased lipolysis and FFAs --> increase in insulin resistance and B-cell dysfunction
41
What are the most important goals for diabetes care when it comes to diet?
Management of glycemia and body weight
42
What two factors tie-in together in maintaining good health?
1. Healthy, balanced diet
2. Physical activity
43
What types of trans fatty acids can you get?
Industrial and ruminant-derived (natural)
44
What are industrial trans fatty acids?
-partially hydrogenated
-converts ~30-50% of cis bonds to trans
-less expensive
-longer shelf life
45
What are ruminant-derived trans fatty acids?
-produced by stomach bacteria
-found in meat and dairy products
-low human consumption
-<0.5% of total energy intake
46
What are the effects of a high trans fatty acid intake?
Increased risk and incidence of heart diseases and diabetes (more likely if predisposed)
47
What can mechanistically induce insulin resistance? (even iff no predisposition occurred beforehand)
High body fat %
High body weight
48
What is the outcome of muscle insulin resistance?
reduced glucose uptake and hyperglycemia
49
What could cause high plasma lipid levels?
Obesity (more adipocytes)
Consumption of TFA
50
What is the lipid theory of induced muscle insulin resistance?
* Obesity = associated with increase in adipose tissue mass and size
* Also associated with raised FFA in circulation
* Trans-Fat increases FA concentration in blood stream
* Leads to accumulation in myocyte cytosol
51
Recall what the insulin-mediated signalling in muscle looks like
NB: phosphorylation of tyrosine residues activates IRS-1
52
Describe the mechansim through which muscle insulin resistance takes place.
* FA accumulation forms lipid derived metabolites such as DAG
* The PKCθ isoform is activated in muscle BY DAGs (presence of DAG results in inhibition of glucose uptake)
* PKCθ is a kinase and phosphorylates IRS-1 on a serine residue
* Inactivation of IRES-1 results in downstream inhibition of kinase cascade which would normally result in glucose translocation
* When cascade = inhibited, GLUT4 translocation = reduced, and glucose uptake = reduced
53
What factor is expressed as a result of high free fatty acids in an obese individual/high fat consuming individual?
Tumour necrosis factor α (TNFα)
54
Why is TNFα expressed?
Due to FFA causing systemic inflammation
55
What is the downstream affect of TNFα secretion?
Decreases AMPK activity and leads to insulin resistance
56
What is AMPK and what does it activate?
AMP-activated kinase
activates energy production and promotes increased GLUT4 translocation
57
Other than glucose oxidation, what else can AMPK stimulate?
Lipid oxidation (mitochondrial fatty acid uptake and oxidation)
58
When the body experiences low energy and AMPK is activated, what does it directly stimulate?
GLUT4 translocation --> Leads too higher glucose metabolism and oxidation
59
How does AMPK promote mitochondrial fatty acid uptake and oxidation?
WHEN AMPK IS ABSENT
1. fatty acids taken up by CPT-1
2. FA entry = limited by malonyl-CoA
3. Malonyl-coA levels are regulated by ACC
4. High levels of Acetyl-coA and ACC = activated --> results
in higher rate of malonyl-CoA formation
5. Thus = higher degree of CPT-1 inhibition and decreased FA uptake
WHEN AMPK IS PRESENT
6. AMPK inhibits ACC, limiting Malonyl-coA
7. More FA uptake and more ATP formed
60
Now we know that AMPK increases glucose and FA uptake into cells. What is the effect of TNFα?
TNFα downregulates AMPK production, thus GLUT4 translocation+glucose uptake, as well as mitochrondrial FA uptake+oxidation is reduced.
This leads to insulin resistance.
61
Describe the findings of this experiment in rats.
* Only lard diet group shows significant increase in TNFα levels
* AMPK = activated by phosphorylation (pAMPK) in Control and Fish Diet,
not in Lard Diet
* Type and composition of dietary fat is therefore important:
--> Lard = rich in saturated fatty acids
--> Fish oil = rich in ω-3 poly-unsaturated fatty acids (PUFAs)
* Relationship is observed between insulin resistance, TNF alpha and AMPK activity in rats fed lard diet
62
What does high fat feeding in rats cause?
Glucose metabolic dysregulation, with alterations in TNFα and AMPK.
63
Excess lipid levels not only effect muscle cells, but hepatic cells too. What is the liver an important regulator of, and what is hyperglycemia caused by wrt the liver?
1. NB regulator of glucose homeostasis
2. Hyperglycemia = caused by increase in glucose production by liver
64
What products released from fat cells contribute to hepatic glucose output during insulin resistance?
Glycerol and FFAs
65
What is the net effect of Glycerol & FFA release from fat cells, on hepatic glucose output?
1. Net increase in intracellular glucose concentration (high liver glucose)
66
In the liver, GLUT2 transport is dependent on what?
Glucose concentration
67
When there is a lot of glucose in the liver, what does GLUT2 do? What happens when liver glucose is increased due to high fat diet?
Exports glucose out from hepatocytes, into circulation
Leads to hyperglycemia
68
Explain this diagram.
1. FFA and Glycerol = released in circulation
2. Glycerol = important substrate for gluconeogenesis
3. FFA [ ] = increased by having a high fat diet
4. FFAs accumulate in hepatocytes resulting in intrahepatocyte conversion into diacylglycerol (DAG)
5. DAG activates PKCε, which decreases phosphorylation of insulin receptor substrate and IRS2
6. A decrease in phosphorylation leads to downregulation of PI3 kinase activity THUS the cascade diminished; Akt is reduced too and its subsequent pathways are reduced also
7. Akt has effect on two downstream signalling pathways: 1. glycogenesis and 2. FOXO-1active (p-FOXO-1 inactive)
8. Glycogenesis is reduced and glucose release is stimulated (increase in plasma glucose)
9. p-FOXO-1= inactive, thus translocates into nucleus and starts gene transcription
involved in gluconeogenesis
10. Results in hyperglycaemia
69
Food rich in refined carbohydrates exerts ________ postprandial glucose levels, compared to those rich in _________ carbohydrates and _______
Food rich in refined carbohydrates exerts HIGHER postprandial glucose levels compared to those rich in COMPLEX carbohydrates and FIBER
70
Does postprandial hyperglycemia exert positive or negative metabolic effects?
Negative
71
What is glycemic index?
GI = refers to the post-prandial glucose response
over 2 h vs. a reference food with same amount of carbohydrate (eg. 50g glucose)
72
What is glycemic load?
73
What is a high GI diet linked with?
T2 diabetes and heart disease
74
Is a LWHF diet or HCLF diet better for T2 diabetes management?
75
What is the correlation between sugar and TAGs?
High sugar intake = increase in TAGs = increase in insulin resistance
76
How do high glucose excursions trigger insulin resistance?
Increased nitrotyrosine is an indication that oxidative stress may play a role in how high glucose induces insulin resistance
77
How is oxidative stress triggered by hyperglycemia?
Production of ROS superoxide
78
How do ROS inhibit insulin functioning wrt DNA?
* High ROS levels damage DNA and other effects
* In response to damaged DNA, enzyme PARP =activated to repair damage
* Secondary effect of PARP = Inhibition of glycolytic enzymes such as GAPDH
* GAPDH inhibition = accumulation of intermediates
* Metabolites also feed into branch pathways called non oxidative glucose pathways
* NOGPs = upregulated (PPP, Polyol, HBP, AGE, PKC)
* Can inhibit insulin functioning
79
How did Sugar-sweetened beverage (SSB) intake alter metabolic circuits & NOGPs in rats?
Changes in SSB animals:
↑ Body weight gain
↑ HbA1c
↑ Cholesterol
↑ Conjugated dienes (early marker of oxidative stress)
80
What happens to beta cell dysfunction as type 2 disease progresses?
Worsens
81
Describe the hyperbolic relationship between b-cell function and insulin resistance
* Degree of insulin resistance matched by elevated
insulin secretion to achieve normoglycaemia in NGT
* As insulin sensitivity diminishes beta cell function
increases
* In overt T2D: Insulin sensitivity even worse but beta cell function declines
82
What are the mechanisms of B-cell compensation?
* Earlier response to insulin resistance
* Mechanisms: hypertrophy and hyperplasia (increased mass,
* synthesis and secretion of insulin)
* Elevated insulin biosynthesis and secretion
* Achieved to match reduced insulins sensitivity and maintain normal glucose tolerance
* Mechanisms triggers by genetic
components, increase
availability of metabolites and
increased incretin action
* All act in concert
83
Why does insulin deficiency eventually occur in type 2 diabetes?
Beta cells are exhausted
84
What does glucolipotoxicity contribute to?
beta cell dysfunction
85
How does glucolipotoxicity contribute to b-cell dysfunction?
* Beta cell compensation to maintain glucose tolerance
* Mechanisms = overabundance of glucose and lipids manifest as glucolipotoxicity
* Exerts various downstream effects
* Beta cell contains GLUT 2 which functions via conc gradient
* Glucose uptake contributes to metabolism and mitochondrial oxidation
* In mitochondria: rates become so high uncoupled respiration
* Uncoupling proteins activated higher flux of protons through UCPs (UCP2) rather than ATP
synthase
* Reduction in ATP generation
* No depolarisation of ATP channel
* Increased ROS and oxidative stress resulting in DNA damage of insulin gene expression
* ROS can also tie to higher apoptosis contributing to a decrease in beta cell mass
* Mechanisms occur in concert contributing to beta cell dysfunction during overt T2D
86
What are the hallmarks of b-cell dysfunction?
1. A decrease in pro-insulin to insulin conversion
2. dysregulated biphasic response
87
Explain how a decrease in pro-insulin is a hallmark of beta cell dysfunction
pro-insulin = decrease in insulin
88
Explain how the dysregulated biphasic response of insulin is a hallmark of beta cell dysfunction
= A decreased 1st & 2nd phase release in individuals with IFG
1st phase is absent
2nd phase is decreased
* UK PDS = reduction in first phase of insulin release with individuals with impaired fasting glucose
* In T2D = first phase release completely absent and second phase release blunted
* Characteristic of progression from impaired
glucose tolerance into overt diabetes where beta cell dysfunction is characterised by disappearance
of first phase and reduced response of second phase
* Consider the mechanisms and constructively think how this occurs and what the molecular
consequences would be.
89
What do you expect the biphasic insulin response in first-degree relatives of individuals with type 2 diabetes to be?
Reduced, also.
* First degree relatives don’t have diabetes may be genetic component
* Clear difference in insulin response
* Lines = first and second phase response
* Note difference in response for each phase
* Both first and second phase response lower in healthy relatives of T2D
* Data potentially points at genetic predisposition for beta cell abnormalities
