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Endocrine System > Pathogenesis of Type 2 Diabetes Mellitus > Flashcards

Pathogenesis of Type 2 Diabetes Mellitus Flashcards

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1
Q

What happens if there is an increase in glucose uptake by tissues?

A

Increased glycogen and protein synthesis and lipogenesis (anabolic)

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2
Q

What is the effect of glucagon produced by alpha cells?

A

Increase of glucose by glycogenolysis and lipolysis

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3
Q

What is diabetes mellitus?

A

A group of metabolic disorders sharing the common feature of HYPERglycemia

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4
Q

What causes HYPERglycemia?

A

Results from a defect in insulin secretion, insulin action (insulin resistance), or both

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5
Q

What organs are secondarily affected by diabetes mellitus?

A

Kidneys,
Eyes,
Nerves,
Blood vessels

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6
Q

What is type 2 diabetes mellitus like?

A

Combination of insulin resistance and beta cell dysfunction

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7
Q

What is the epidemiology of type 2 diabetes mellitus?

A

346 million people worldwide, according to WHO

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8
Q

What is the cause of diabesity epidemic?

A

Increase of sedentary lifestyle with poor eating habits

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9
Q

What is the mortality rate with middle and low income countries?

A

80% of deaths are diabetic related deaths

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10
Q

What is the % of population suffering from diabetes in Qatar?

A

17%

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11
Q

What are the risk factors for type 2 diabetes mellitus?

A

Multifactorial complex disease due to interaction between:
1. Genetic factors
2. Environmental factors
3. Inflammation

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12
Q

Which type of diabetes is associated with autoimmunity?

A

Type 1

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13
Q

What is the disease concordance rate in monozygotic twins?

A

80 to 90%

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14
Q

What is the association between the risk and first degree relation?

A

Risk is 5 to 10x higher in first-degree relatives

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15
Q

What are the environmental factors that effect diabetes?

A

Obesity –> the most important one
Sedentary lifestyle –> independent from obesity
Weight loss & exercise have additive effects –> improve insulin sensitivity

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16
Q

What is the metabolic defect in DM?

A

Lower response of peripheral tissue (like skeletal muscle, adipose tissue, and liver) to insulin
This leads to insulin resistance

Inadequate insulin secretion due to insulin resistance & hyperglycemia –> beta cell dysfunction

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17
Q

What does insulin resistance mean for skeletal muscles?

A

Decrease in glucose transport
Decline in glycogen synthesis
Increase in protein breakdown

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18
Q

What does insulin resistance mean for adipose tissues?

A

Impaired insulin-stimulated glucose transport
Impaired inhibition of lipolysis

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19
Q

What does insulin resistance mean for the liver?

A

Continues gluconeogenesis
Increased glucagon
Increased glycogenolysis
Stimulates fatty acid synthesis

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20
Q

How does insulin resistance occur in the liver?

A

Failure to inhibit endogenous glucose production (gluconeogenesis occurs in the liver) –> High Fasting blood glucose

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21
Q

How does insulin resistance occur in skeletal muscles?

A

After meal –> failure of glucose uptake and glycogen synthesis in skeletal muscle –> High postprandial glucose

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22
Q

How does insulin resistance occur in adipose tissue?

A

Failure to inhibit hormone-sensitive lipase in adipose tissue –> Increased free fatty acids –> more insulin resistance

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23
Q

What is the most important factor in insulin resistance?

A

Obesity, amount and distribution of body fat (central vs peripheral)

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24
Q

How does obesity cause insulin resistance?

A

Excess-free fatty acids, released due to lipolysis (central lipolytic fat), will be taken by the liver and muscle –> Increased intracellular triglyceride & FA metabolites are potent inhibitors of insulin signaling –> Insulin resistance

In obesity (excessive adipose tissue), there is an increase in adipokines, which promote hyperglycemia & decrease adiponectin –> Insulin resistance

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25
What is the function of adiponectin?
To increase insulin sensitivity
26
How does inflammation lead to insulin resistance?
Free fatty acids --> proinflammatory cytokines --> Inflammatory milieu that results in both insulin resistance and beta cell dysfunction
27
What is the association between insulin resistance and genetic susceptibility (normoglycemic offspring)?
Normoglycemic offspring of parents with type 2 diabetes have reduced nonoxidative glucose metabolism associated with reduced muscle glycogen synthesis. IR presents years before the onset of hyperglycemia. Increased intracapsular lipid content has been identified in these IR offsprings
28
What does the increase in IC lipid content on IR offsprings indicate?
Dysregulation of fatty acids metabolism may mediate metabolism, in a study, this dysregulation appeared to be due to an inherited defect in mitochondrial function
29
What is the beta-cell dysfunction mechanism?
An increase in free fatty acids affects beta cells --> decreases insulin release (lipotoxicity)
30
What effects does the beta cell dysfunction have?
Impact on chronic hyperglycemia Abnormal incretin effect reduces secretion of insulin Amyloid deposition within islet cells Abnormal genes control insulin secretion
31
What are the beta cells like in the early stages of insulin resistance?
Beta cells try to compensate, so there is hypertrophy and hyperplasia. Insulin secretion by beta cells is increased, and the blood glucose levels are normal to impaired glucose tolerance
32
What are the beta cells like in the late stages of insulin resistance?
There is beta cell failure --> hypoplasia and hypotrophy, accumulation of islet amyloid polypeptide (amylin) Decreased insulin secretion by beta cells Blood glucose levels --> DM
33
What are the metabolic effects of decreased or no insulin on carbohydrates?
Decreased glucose uptake by muscle and adipose tissue Increased glycogenolysis Increased gluconeogenesis
34
What are the metabolic effects of decreased or no insulin on lipids?
Increased lipolysis Increased fatty acid oxidation
35
What are the metabolic effects of decreased or no insulin on proteins?
Decreased protein synthesis Increased protein degradation
36
What is the common population that is affected by Type 2 diabetes?
Usually obese adults > 40yo Nowadays, there is an increase seen in children and adolescents (because of the sedentary lifestyle)
37
What are the clinical features of DM?
A lot of cases are asymptomatic --> silent Fatigue, blurred vision and dizziness Triad of polyuria, polydipsia, and polyphagia Acanthosis nigricans
38
What causes acanthosis nigricans in DM?
Excess insulin causes skin cells to reproduce at a rapid rate and more melanin deposited
39
What causes the triad of polyuria, polydipsia and polyphagia?
Lipolysis --> the breakdown of fat (adipose tissue) Breakdown of protein (skeletal muscle) --> Weight loss and hunger In the kidneys: osmotically active --> more urination --> dehydration --> increased thirst
40
In the absence of unequivocal hyperglycemia, what is the criteria for diagnosis?
Requires two abnormal test results from the same sample or in two separate test samples
41
What is prediabetes?
Impaired glucose tolerance
42
What is the criteria for diagnosing pre-diabetes?
Fasting glucose between 100 and 125 mg/dL or 2-hour plasma glucose between 140 to 199 mg/dL during OGT and/or HbA1C between 5.7% to 6.4%
43
What is the % of pre-diabetic patients that will develop diabetes in the next 5 years, given that they have obesity and a family history?
25%
44
What is Hyperosmolar Hyperglycemic Syndrome (HHS)?
An acute metabolic complication
45
What is the pathogenesis of HHS?
Hyperglycemia, which will lead to glycosuria (due to osmotic diuresis), which leads to the loss of water and electrolytes, which then leads to dehydration and hyperosmolarity and eventually impaired renal function --> HHS
46
What are the clinical manifestations of HHS?
Thirst, polyuria, lethargy, focal neurological deficits (seizures, for instance), coma and death
47
What is insulin levels like in HHS?
Insulin is still present, no lipolysis and no ketoacidosis
48
What is the affected population of HHS?
Patients are usually old with stroke or infection, have no adequate fluid intake & no symptoms of diabetic ketoacidosis, so delayed medical attention
49
What are common symptoms of diabetic ketoacidosis?
Nausea, vomiting and respiratory difficulty
50
What is hypoglycemia?
Blood glucose levels are lower than normal
51
What might cause hypoglycemia?
Missing a meal, excessive physical exertion or excessive insulin administration
52
What are the clinical manifestation of hypoglycemia?
Dizziness, sweating, palpitations, and tachycardia --> loss of consciousness
53
How do you treat hypoglycemia, and why?
Oral or IV glucose intake to prevent neurological damage
54
What are chronic complications of Type 2 diabetes?
Diabetic Macrovascular Disease Diabetic Microvascular Disease
55
What is diabetic macrovascular disease, and what can it lead to?
Medium and large vessels affected Accelerated atherosclerosis, MI, and stroke Peripheral vascular disease --> gangrene of lower extremities --> non-traumatic amputation
56
What are the presentation of diabetic macrovascular disease?
They usually have hypertension and dyslipidemia
57
What are the different examples of diabetic microvascular disease?
Diabetic retinopathy Diabetic nephropathy Diabetic neuropathy
58
What causes the formation of advanced glycation end products (AGEs)?
Nonenzymatic glycation reaction between glucose-derived precursors and proteins. AGEs bind to RAGE receptors
59
Where are RAGE receptors found?
On inflammatory cells, endothelium and vascular smooth muscle
60
What are the effects of the AGE-RAGE interaction?
1. Cytokine release, such as TGF-β, leads to excess basement membrane material and VEGF (diabetic retinopathy) 2. Reactive oxygen species in endothelial cells --> inflammation 3. Increase in procoagulant activity on endothelial cells (endothelial dysfunction) & enhance proliferation of vascular smooth muscles and extracellular matrix formation
61
What do AGEs also cross link, what is the effect of that?
Extracellular matrix proteins which can trap LDL in large vessels --> accelerated atherosclerosis Albumin in capillary wall --> microangiopathy
62
What is the effect of activation of protein kinase C?
Production of the proangiogenic molecule as VEGF, implicated in neovascularization leading to diabetic retinopathy
63
What is the effect of polyol-induced susceptibility to oxidative stress?
IC glucose is converted to sorbitol to then fructose, which water influx to increase, which then causes osmotic injuries like peripheral neuropathy and cataract
64
Which enzyme converts glucose to sorbitol?
Aldose reductase
65
What substances does the polyol-induced susceptibility to oxidative stress reaction require?
NADPH, but NADPH is also required for the generation of reduced glutathione, which is an important antioxidant, persistent IC hyperglycemia through reduction of GSH makes nerve cells susceptible to oxidative stress
66
What is the effect of overload of hexosamine pathway?
Increase in fructose 6 phosphate, which causes excess proteoglycans and thus end organ damage
67
What is seen in diabetic nephropathy?
1. Glomerular lesion: thickening of glomeruli capillary BM, diffuse mesangial sclerosis & nodular glomerulosclerosis 2. Renal hyaline arteriosclerosis (afferent & efferent) & atherosclerosis 3. Pyelonephritis and necrotizing papillitis
68
What will the diffuse mesangial sclerosis eventually result in?
Nephrotic syndrome
69
What will nodular glomerulosclerosis eventually lead to?
Kimmelstiel - Wilson disease
70
What is the earliest manifestation of diabetic nephropathy?
Microalbuminuria --> overt macroalbuminuria & decreased GFR --> ESRD
71
What is the appearance of nodular glomerulosclerosis?
Nodules of pink hyaline material form in regions of glomerular capillary loops in the glomerulus
72
What causes the formation of nodules in nodular glomerulosclerosis?
A marked increase in mesangial matrix from damage as a result of non-enzymatic glycosylation of proteins --> pathognomic of diabetes --> PAS positive
73
Which pathway does diabetic neuropathy occur through?
Polyol pathway (osmotic damage to Schwan cells), or direct axonal damage
74
What are the clinical manifestations of ascending distal symmetric sensorimotor polyneuropathy?
Numbness, loss of pain sensation, difficulty in balance, paresthesia
75
What are the clinical manifestations of ANS dysfunction?
Postural hypotension, bowel & bladder function disturbance, sexual dysfunction
76
What are the clinical manifestations of diabetic mononeuropathy?
Foot drop, wrist drop or cranial nerve palsy
77
What is the reason behind cataract in diabetic patients?
Opacification of the lens due to the conversion of glucose to sorbitol --> osmotic damage
78
What are the different types of retinopathy?
Proliferative and non-proliferative retinopathy
79
What is non-proliferative retinopathy?
Retinal hemorrhage, retinal exudate (hard or soft), microaneurysm, venous dilation, edema, and thinking of retinal capillaries (microangiopathya)
80
What is proliferative retinopathy?
Neovascularization and fibrosis, vitreous hemorrhage, and retinal detachment
81
What is HbA1C test?
The most widely used clinical test to estimate glycemic control in the last 8 to 12 weeks. Correlate mainly with microvascular complications
82
What is the purpose of the HbA1C test?
To diagnose diabetes (≥6.5) and to monitor treatment (≤7)
83

Endocrine System (25 decks)

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