Introduction to Diabetes Flashcards
Define diabetes mellitus
Metabolic disorder characterized by elevated blood glucose concentrations and disturbances of carbohydrates, lipids and protein due to defective insulin secretion and/or action.
(T/F) Diabetes is only related to deregulation in CHO metabolism
FALSE - involves fats and protein
Characteristics of T1DM
- Insulin-dependent (needed for survival)
- Typically diagnosed early, prior to 20 y/o
- Ketosis prone
Why is T1DM ketosis prone?
Due to the absolute deficiency of insulin
Characteristics of T2DM
- Non-insulin dependent
- Maturity onset (diagnosed later)
- Not prone to ketosis
Why is T2DM NOT prone to ketosis?
There is NOT an absolute deficiency of insulin
(T/F) In T2DM, there is a lack of insulin
F - there is a lack of action of insulin
What is gestational diabetes? When is it resolved?
Diabetes diagnosed during pregnancy, usually resolved after the delivery of the baby
What are some other causes of diabetes?
- Genetic defects (CF)
- Pancreatopathy
(T/F) Pre-diabetes is often recognized as a real diagnosis, as it is not possible to intervene early to delay or prevent T2DM
FALSE - diagnosing prediabetes is extremely important to prevent or delay T2DM
Pathophysiology of T1DM (Brief)
Auto-immune or idiopathic destruction of pancreatic b-cells, which results in an absolute deficiency of insulin production.
-This happens QUICY (few months to a year)
Pathophysiology of T2DM (Brief)
-Calls experience insulin resistance, and are responding abnormally and will not utilize glucose efficiently, leading to hyperglycaemia.
(T/F) In T2DM, insulin resistance refers to the absence or blockage of insulin
False - insulin resistance means that the insulin signalling is not functioning as normal, and glucose is not being taken up as efficiently.
What causes hyperinsulinemia in T2DM?
When there is hyperglycaemia, the pancreas may compensate in producing more insulin (requires more insulin to reach the same basal blood glucose levels)
What happens with chronic hyperinsulinemia?
Eventually, the b-cells will start to reduce their insulin secretion
Typically, out of 100 diabetic people ____ will have T1DM and the rest will have T2DM
5-10%
Type 1 patients always require ____
Insulin treatment
Out of the patients who are T2DM and who are ketone prone will require what?
Insulin treatment
Only about 5%
____ of T2DM patients are Ketosis resistant
85-90%
Out of the ketosis resistant (No insulin Rx) T2DM patient, what % are normal weight? Obese?
10% normal weight
75-80% Obese
What will T2DM, ketosis resistant, obese and normal weight patients require as medications?
- 25% Diet Rx
- 25% Insulin Rx
- 50% Oral medication Rx
(T/F) T2DM never have insulin treatment
False, 25% typically treated with insulin
How many Canadians over 12 y/o reported being diagnosed with diabetes?
- 0 milllion
6. 7%
____ are more prevalents than ____ in terms of diabetes diagnosis
Males
Females
What increasing with age?
Incidence of diabetes
What is the most important risk factor for diabetes?
Age
What is the key point of the graph depicting diabetes increasing with age
Diabetes in both males and females drops after 12 y/o, then steadily increases. Males always more prevalent than females
Which province has the most diabetes? The least?
- Ontario, Maritimes
- Alberta
Which populations are at a higher risk for developing diabetes (while living in Canada)?
- South Asian, Asian, African, Hispanic descent
- Overweight, older and lower income individuals
Which population poses a significant higher risk (3-5x) for developing diabetes?
Indigenous populations
(T/F) The increased risk of diabetes for certain populations is primarily due to genetics
F - while genetics may have a small role, is more often related to lack of access, healthy foods, health care and nutritional education
What are very important contributors to the development of diabetes within the population?
Overweight, older and lower socioeconomic status
What is the trend of obesity and diabetes in the states?
Obesity comes first, where diabetes in the same population arrives later (Diabetes follows obesity)
A large proportion (~27.4%) of people have ____ diabetes
undiagnosed
What is the danger of living with undiagnosed diabetes?
People will live many years with uncontrolled blood sugar which can have detrimental effects
(T/F) T2DM often takes a while to diagnose
True
Currently ___ people live with diabetes, where where complications often take awhile to manifest
1/2
Causes of T1DM?
- For an unknown cause, body will begin to produce islet cell auto-antibodies
- These auto-antibodies will destroy the B-cells, causing injury and decreasing levels of insulin and eventually inhibiting any insulin secretion.
What are some triggers that are considered to begin the production of auto-antibodies?
- Genetic predisposition (unsure of the actual gene)
- Environmental triggers, such as virus, toxins and stress
Symptoms of T1DM?
-Polydipsia, polyuria, polyphagia, weight loss
Symptoms of T2DM?
-Polydipsia, polyuria, polyphagia, weight-gain
(T/F) Symptoms are much more severe in T2DM
False, much more severe in T1DM
What will clinical lab values show in both T1 and T2 DM?
- Glycosuria
- Hyperglycemia
- Abnormal glucose tolerance
What actions does insulin increase?
- Increase glucose uptake and storage
- Increase lipogenesis
- Increase protein synthesis
What actions does insulin decrease?
- Decrease glycogenolysis and gluconeogenesis (endogenous glucose production)
- Decreased lipolysis
- Decreased proteolysis
What is the main role of insulin in the liver?
Glucose production
(T/F) In the liver, insulin has less or a role in the regulation of glucose
T
While liver controls glucose production under the influence of insulin, what are insulins effects on heart, adipose and muscle?
Stimulate glucose intake (GLUT4 dependent)
(T/F) Insulin will stimulate hepatic uptake of glucose
False, as liver is not GLUT4 dependant
Explain the effects of insulin deficiency on glucose metabolism
- Higher hepatic endogenous production of glucose + no glucose uptake into cells = hyperglycemia.
- Cells feel starved, and will signal hunger (polyphagia)
- Glucose threshold is reached in blood, spill-over into the kidney (polyuria)
What are the long-term effects of uncontrolled diabetes on glucose metabolism?
Will lead to polyuria and dehydration.
What may dehydration lead to? (3) Which ones lead to death?
- Polydipsia
- Cellular shrinking which could lead to nervous system malfunction (death)
- Decrease in blood volume which could lead to renal failure, low cerebral blood flow (death)
Explain the effects of insulin deficiency on lipid metabolism
- Less lipogenesis and less synthesis of TGs from dietary fat, promoting lipolysis.
- Increase in FFA in bloodstream will be alternative source of fuel, leading to ketosis.
Is the ketosis caused by insulin deficiency (lipid metabolism) dangerous?
- In a healthy person, ketosis is not dangerous however in a diabetic person may develop into metabolic acidosis if prolonged.
- Levels of ketones may be seen 10x as high than normal ketosis (if uncontrolled)
What are the effects of the high levels of ketone bodies caused by insulin deficiency (lipid metabolism) ?
- Increased ventilation to excrete CO2 (acidic)
- Decrease pH and metabolic imbalances could eventually lead to diabetic coma.
When are most people diagnosed with T1DM?
After an episode of diabetic coma
Effects of insulin deficiency on protein metabolism?
-Less AA uptake by the cells, and increased protein catabolism –> Muscle wasting and weight loss
How do all the macromolecules contribute to hyperglycaemia?
Due to the catabolic state, glycerol (from TG) and gluconeogenic AA will participate in gluconeogenesis, further aggravating the hyperglycaemic state.
What happens in the exacerbated fasted state due to a lack of insulin? (fuel flux)
- Full blown lipolysis, where large amount of FFA in blood, and glycerol –> glucoe.
- Increases proteolysis, used in gluconeogenesis or protein catabolism (neg nitrogen balance)
What are the main sources of fuels in the exacerbated fasted state?
Glucose is being produced at it’s highest rate alongside the production of keto acids from the liver.
In T1DM, the person is better off ____ than eating
fasting
How does the fed state aggravate the fuel flux?
Recall that a already amount of glucose and keto acids are already being produces, and protein catabolism increases.
- Lack of insulin means that we are further aggravating the hyperglycaemic state in the bloodstream
- Glucose not taken up, protein not used for pro synthesis and lipids are catabolized
(T/F) In the fed state, some of the excess glucose will be synthesized into glycogen in T1DM
False, as insulin is deficient
How is T1DM often rapidly diagnosed? How is someone relived from a diabetic coma?
- Blood sugar ~25 mmol/L
- Immediate infusion of IV insulin, electrolytes (Na+/K+)
What is a major cause of T2DM?
Obesity, often from excessive food intake, lack of PA, some genetic predisposition
Explain the vicious cycle of insulin resistance and obeisty
Obesity can cause insulin resistance, which will lead to hyperglycemia and hyperinsulinemia. The excess insulin may cause further weight gain, aggravating obesity.
What associated with obesity may also contribute to insulin resistance?
Inflammation, as there is low-grade inflammation on obesity
What does insulin resistance lead to ? (2)
- Hyperglycemia
- B-cell decompensation
What can genetic predisposition influence?
- Obesity
- Insulin resistance
- B-cell decompensation
Over time, what will aggravate B-cell decompensation, eventually leading to T2DM?
- Insulin resistance
- Hyperglycaemia
- Lipotoxicity, inflammation
- Some genetic predisposition
We know that intake of sugar that does not lead to weight gain, is NOT the cause for diabetes. However, what may influence insulin resistance?
High fructose corn syrup from soft-drinks can contribute to insulin resistance even when consumed within energy balance.
(T/F) We could develop diabetes on a high fat diet
T
Explain why when insulin resistance is diagnosed, it is not yet indicative of T2DM
The hypersinsulinemia will work to control blood glucose
When do we officially develop diabetes?
When there is B-cell destruction and the pancreas can no longer compensate with increased insulin secretion
What is lipotoxicity?What can is lead to?
- High level of lipids within the circulation which impacts cell function and inflammation
- B-cell decomposition
Define insulin resistance
Lesser sensitivity to insulin actions in suppressing hepatic glucose production and stimulating glucose uptake
(T/F) Insulin resistance is typically due to a defect in the receptor
False, issues with the downstream signalling processes
Which organs can function regardless of insulin resistance? Why?
-Brain, liver , RBCs
Not dependent on insulin (non GLUT4)
Briefly explain the mechanism of action of insulin binding
Insulin will bind to ITK induce conformational change and allow fo the translocation of glucose transporter to the membrane from the cytoplasm
What intracellular signalling pathways will insulin activate?
- MAPK
- PI3K
What are the outcomes of the MAPK pathway?
-Cellular growth and differentiation and survival
What are the outcomes of the P13K pathway? How does it act?
Impart the AKT-PDK-1 pathway under the control of mTORC2
-Cyclic action
How is SPREBP1c activated?
Through mTORC1, under control of Akt-PDK-1 (P13K)
What are the effect of the PDK-1 AKT pathway on muscle?
-Increase glucose transport and glycogen synthesis
What are the effect of the PDK-1 AKT pathway on liver?
Increase glycogen synthesis, lipogenesis, decrease gluconeogenesis
What are the effect of the PDK-1 AKT pathway on adipose tissue?
Increase glucose transport, lipogenesis while decreasing lipolysism
What is the implication of the P13K (which controls Akt-PDK-1) being cyclic?
We know that we will have a certain amount of insulin in the blood after each meal, meaning these processed are consistent after each meal.
Differentiation the actions of mTORC1 and mTORC2
- mTORC1 will be ativated by AKT to activate SREBP1c
- mTORC2 will activate AKT
Risk factors for T2DM?
- Age
- Male sex
- Obesity
- Sedentary lifestyle
- Ethnicity
- Prediabetes
- Family history
- PCOS
What are some risk factors for T2DM implicated in pregnancy?
- Gestational diabetes
- Child of women with poorly controlled diabetes during pregnancy
- Low birth weight (<2.5 kg ) and high birth weight (>4kg)
What are some conditions commonly associated with insulin resistance?
- Sleep apnea
- Infections
- Chronic steroid use
- Cushings syndrome
- Hemochromatosis
- Lipodystrophic diabetes
- Acanthosis nigricans
- Werners syndrome
- Idiopathic
Explain the metabolic staging of T2DM that is reversible
- Insulin resistance, often as a consequence of obesity results compensatory hyperinsulinemia. When the hyperinsulinemia is no longer sufficient, will lead to hyperglycemia.
- Hyperglycemia will lead to impared glucose tolearance, IFG which can lead to b-cell defects.
- Once insulin secretion drops off - indicative of early diabetes.
Up to what point is the metabolic progression of T2DM reversible?
Early diabetes - b-cell defects and decreased insulin secretion
When is T2DM non-reversible?
When b-cell defects escalate to b-cell failure , and development of late diabetes
How can the metabolic stages, up to early diabetes, become reversed?
-Weight loss, exercise, diet and medication.
Compare & contrast the onset of T1DM vs T2DM
T1: Sudden, <25 y/o, lean, minor family history
T2: Gradual, 90% obese, marked family history
Compare & contrast the symptoms of T1DM vs T2DM
T1: Severe, wasted, 3Ps, HLA, antibodies
T2: Less evident, obese, fatigues, vision changes, weight loss, no HLA or antibodies
(T/F) Weight loss will only occur in T1DM
F - some weight loss may be present in T2DM patients
Compare & contrast the control of T1DM vs T2DM
T1: Difficult, small changes in insulin, exercise or diet greatly affect BG control
T2: Easier, rapid changes in glucose not observed
Compare & contrast the stability of T1DM vs T2DM
T1: Unstable, regulation of food/insulin dosing crucial
T2: Easily stabilized
Compare & contrast ketoacidosis in T1DM vs T2DM
T1: Frequent, develops if insufficient insulin
T2: Rare
Compare & contrast the effectiveness of oral anti-hyperglycemic agents in T1DM vs T2DM
T1: Not effective
T2: Effective
Compare & contrast the use of Insulin Rx in T1DM vs T2DM
T1: Necessary bc of islet cell loss
T2: 20-30% need insulin
Compare & contrast the importance of diet in T1DM vs T2DM
T1:Very important, but control may be difficult
T2: Important and possibly the only treatment necessary
Compare & contrast the complications of T1DM vs T2DM
T1: Vascular complications after 5 yr Dx
T2: May occur if poorly controlled
What are some short-term complications of diabetes?
- Hypoglycemic epidoses
- Diabetic ketoacidosis
- Respiration and cognitive changes
- Hyperglycemic hyperosmolar syndrome
Diabetic ketoacidosis is ____ and is seen mostly in ____
Life threatening
T1DM
What increases risks of diabetic ketoacidosis? Symptoms?
- T1DM, illness, infection, stress
- N/V, stomach pain, acetone breath, rapid
When does hyperglycemic hyperosolar syndrome occur? What may trigger it?
- More in T2Dm with BG > 33mmol/L
- Dehydration, infection
At what BG is hypoglycemia defined?
<3.9 mmol/L, but may vary per individual
Symptoms of hypoglycemia?
- Neurogenic (sweating, shaking, tachycardia, anxiety, hunger)
- Neuroglycopenic (weakness, confusion, blurred vision, loss of consiousness)
Common etiologies of hypoglycemia?
- Skipping/delaying meals
- Reduced CHO intake without adjusting insulin
- Misdosage of insulin
- Unplannned exercise
What is the 15-15 rule for treatment of hypoglycemia?
Give 15 g of fast-absorbed CHO, check BG 15 mins later and repeat if BG still low
How can care provider (or patient) treat severe hypoglycemia?
Injection of glucagon or glucose
What are some long-term complications of diabetes?
Micro and macrovascular damage
Examples of retinopathy damage?
-Cataracts, glaucoma, macular edema which can lea to blindness
Examples of nephropathy damage?
Found in 20-40% of diabetics, very common and could lead to CKD/failure, requiring dialysis or transplantation
Examples of neuropathy damage?
~50% with DM
-Impaired sensation or pain in extremities, may require amputation
Which kind of neuropathy damage will lead to decreased peristalsis, less intestine mobility and nausea?
Gastroparesis
What are common macrovascular damages that occur in DM?
-CVD, CHD and stroke
What are other macrovascular damages that occur in in DM?
-Poor wound healing, erectile dysfunction, increased susceptibility of infections
What is the pathophysiology of micro and macrovascular complications?
Glucotoxicity and lipotoxicity (from deregulation in metabolism) and glycated proteins will create endothelial damage, which will accelerate plaque formation/atherosclerosis, which will lead to HTN< thrombosis, ischemic end-organ damage.
What is A1C?
Glycated hemoglobin
How is A1C measured? What is the normal target?
% of total Hb in circulation
4.3-6.0% in healthy individuals
Why is A1C a preferred measurement over blood glucose?
Indicator of long-term glucose control, as Hb has a 1/2 life of 3 months.
Dyslipidemia in T1DM?
- HyperTG
- HDL and LDL-c may be normal
Explain hyperTG in T1DM
As there is a deficiency in insulin, there is decreased LPL activity (insulin dependent) thus - less hydrolysis of TGs from chylos and VLDLs
How can hyperTG in T1DM usually be reversed?
With insulin injections
Dyslipidemia in T2DM?
- HyperTG
- Low HDL-c
- LDL-c ma be elevated or normal
Explain hyperTG and low HDL in T2DM
Increased de-novo synthesis of TGs from glucose and FFA, and more TGs packed into VLDLs, which will increase CETP exchange in HDL and HDL will be taken up by hepatic lipase.
What is the main characteristic of diabetic lipid profiles?
Hyper TG
What is a key concept regarding diabetes and CVD?
Diabetic patients have 2-4x risk of developing CVD - which is a GREATER independant risk than smoking, HT, hypecholesterolemia, obesity
What has the greatest impact on endothelial damage?
Chronically high glucose levels
What account for 65% of deaths in diabetic patients?
CVD
Explain the difference between assessing risk factors and screening
Risk factors will determine if the patient should be screened, or screened more often
-Screening is usually done through a blood test
Name some key points from the CANRISK questionnaire
1) Risk of diabetes goes up with age
2) BMI and waist circumference can affect risk of diabetes
3) Level of PA and diet can affect risk of diabetes
4) High BP, BG and pregnancy can be associated with DM
5) Some genetic components, and level of education may influence DM
According to DC Clinical Practice Guidelines, which risk factors should be assessed annually fo T2DM?
- Family history
- High risk populations
- History of GDM/prediabetes
- CVD risk factors
- Presence of end-organ damage
Patient w/no risk factors, age <40 y/o with low/mod risk?
No screening needed
Patient w/ no risk factor, but age 40 y/o or older with high risk (CANRISK)?
Screen every 3 years
What classifies a high risk patient (CANRISK)?
33% chance of developing T2DM within 10 years
Patient has risk factors OR very high-risk (according to CANRISK)
Screen every 6-12 months
How is screening conducted?
1) Fasting plasma glucose (No caloric intake for at least 8 hours)
2) A1C%
FPG 6.1-6.9 mmol/L ?
IFG
FPG >/= 7.0 mmol/L ?
Diabetes
A1C 6.0-6.4%?
Pre-diabetes
A1C >/= 6.5%?
Diabetes
Patient is asymptomatic (No 3Ps) and presents with FPG or A1C within the diabetes range, what next?
Repeat A1C or FPG to confirm
Patient presents with FPG and A1C, where only one is in the diabetes range, what next?
Repeat test that gave diabetes range to confirm
Patient presents with FPG and A1C within diabetes range, what next?
Diabetes confirmed.
(T/F) In a patient with symptoms of overt hyperglycaemia, one test within the diabetes range (A1C, FPG, 2hPG, random PG) can diagnose diabetes
T
Patient presents with random PG of >/= 11 mmol/L?
Diabetes confirmed
When will a single test be indicative of diabetes?
1) If patient presents with symptoms
2) If test is random plasma glucose
Explain how a OGTT is done
Blood glucose level is measured before drinking a 75 g glucose drink, where the blood glucose response is compared over a standard response
When is blood glucose measured after the ingestion of the 75 g glucose drink?
After 2 hours ( after peak), and it will be measured against the cut-offs for glucose intolerance or Type 2 DM
Describe the normal blood glucose curve
Begin at a normal FBG (~ 5 mmol/L), and will peak around 1 hour (~8 mmol/L) then decrease to baseline levels after 3 hours
Describe the IGT blood glucose curve
Normal fasted blood glucose levesl, but reached a peak of ~11 mmol/L after 1 hour, and takes longer to return to baseline levels
Describe the T2DM blood glucose curve
Fasted glucose begins at a higher level (~8mmol/L) and will peak at 1 hour at ~14 mmol/L, and will take longer to return to impaired baseline values.
What does the OGTT blood glucose curve tell us?
We can see the chronic large amounts of glucose that the bloodstream is exposed to based on of the size of the area under the curve.
What is the issue with having a large response of blood glucose at each meal in IFG and DM?
If this happens at each meal, our bloodstream is chronically exposed to a large amount of glucose in the bloodstream frequently throughout the day
(T/F) Metformin may be prescribed to help prevent the worsening of diabetes in pre-diabetic patients
T
What was the result in the Diabetes Prevention Program (DPP) study when pre-diabetics received Metformin?
Incidence of diabetes decreased by 31%
What was the result in the Diabetes Prevention Program (DPP) study when pre-diabetics were subject to lifestyle interventions
Incidence of diabetes decreased by 58%
What was the bottom line of the DPP study?
Enough evidence that shows we should intervene with life-style and medications (metformin) with a diagnosis of pre-diabetes
What is recommended for vascular protection for all patients with daibetes?
ABCDESSS
A?
A1C - optimal glycemic control = 7%
B?
BP - optimal BP control (< 130/80 mmHg)
C?
Cholesterol - LDL-C < 2.0 mmol/L if decide to treat
D?
Drugs to protect the heart (ASA –> ACEi or ARB, Statin, ASA if indicated)
E?
Exercise/Eating
Sx2?
- Smoking cessation
- Screening
- Self-care management
Explain the rational for setting a target A1C higher for DM patients compared to healthy individuals
We want to bring diabetic patients into a healthy zone for the, which is not necessarily the non-diabetic target. There also needs to be a risk-benefit assessment between the effectiveness of meds and side-effects.
What is a major side effects of most anti-hyperglycemic meds? What is the goal?
Hypoglycemia
We want to control blood glucose in an optimal range while avoiding hypoglycemia
A1C target for MOST patients with T1 or T2 DM?
~7%
Liberal A1C target for those with limited life expectancy, high level of functional dependency, CAD, ischemic events, history of hypoglycemia?
7.1-8.5%
When could a target A1 C be considered for T2DM patients?
To further lower the risk of nephropathy and retinopathy, but must be balanced against the risk of hypoglycemia
What is the normal target A1C range for healthy individuals?
4.3-6.0%
Suboptimal A1C to consider action?
7.1-8.5%
Inadequate A1 action required?
> 8.5%
Normal FG?
3.9-5.6 mmol/L
Optimal FG (DM target?)
4.0-7.0 mmol/L
Suboptimal FG (consider action?)
7.1-10 mmol/L
Inadequate FG (action required?)
> 10 mmol/L
Glucose 2hr PC ideal (non DM)?
4.4 - 7.0 mmol/L
Glucose 2 hr PC optimal DM target?
5.0-11 mmol/L
Glucose 2 hr PC Suboptimal (consider actions?)
11.1-14.0 mmol/L
Glucose 2 hr PC inadequate (action required?)
> 14.0 mmol/L
When should monitoring of BG be increases?
More often in severe cases, new cases, exercise and illness
How can a patient know their own target blood glucose?
If the patient SMBG when they feel symptoms of hypoglycemia, can find the blood glucose level that should be avoided
What may be monitored?
- SMBG (finger prick)
- Blood glucose
- Urine glucose
- Blood ketones
- Urine ketones
- Glycated proteins
How are glucometers used?
Daily monitoring, usually used for Type1 and variable for type2. Important to prevent hypoglyemia
When are glucometer advised?
When patient on anti-hyperglycemic Rx or Insulin Rx, not usually recommended if diet Rx only
