Diabetes Flashcards
Diabetes is associated with increased risk of what condition ?
Atherosclerotic cardiovascular disease
Diabetes is a leading cause of which diseases ?
Renal failure
Adult blindness
Non-traumatic lower limb amputation
EXplain the glucose homeostasis and role of insulin
-Glucose transport across membranes is mediated by glucose transporters or GLUTs (over 10 different types).
-GLUT2 is an example of an insulin-independent transporter –it does not rely on insulin to transport glucose into cell. (Other insulin independent transporters are GLUT1 and GLUT 3 – which transport glucose into liver and brain cells.)
- GLUT2 is found on beta-cells of the pancreas and are responsible for glucose sensing and subsequent insulin secretion
- When glucose is around it enters the beta-cell via GLUT2, is converted to pyruvate and eventually ATP/ADP which close an ATP-sensitive potassium channel
- Closing of the channel, prevents movement of K out of cell resulting in depolarization of the cell membrane and opening of voltage-gated calcium channels. The influx of calcium subsequently leads to exocytosis of insulin.
-Glucose enters muscle cells and adipocytes via GLUT 4 (which is an example of an insulin-dependent transporter).
-Muscle is a principal storage site for glucose (in form of glycogen), as well as adipose tissue where glucose is converted into triglycerides for storage. Without insulin, glucose is unable to enter these tissues.
- At these sites, insulin binds to insulin receptors and signals the cell to insert GLUT 4 transporters into the cell membrane, allowing glucose entry and either immediate utilization or for protein/glycogen/lipid synthesis (storage for later).
Insulin has additional gene expression and growth regulator effects.
Explain the pathogenesis of DM
type 1 = absolute deficiency of insulin
T2= relative deficinecy (too little insulin for the amount required or resistance to insulin present)
Normal regulation in a person without DM:
- Insulin, produced by the beta cells of the pancreas, increases uptake of glucose into muscle and fat cells – thereby decreasing plasma glucose concentrations.
- Glucagon is the counter regulatory hormone to insulin. It is produced by the alpha cells in the pancreas, and it increases serum blood glucose concentrations by converting stored glycogen in the liver to glucose (a process known as glycogenolysis), inhibiting glycolysis (the breakdown of glucose), and promoting gluconeogenesis (the new formation of glucose).
- Increases in blood glucose that stimulate increase in insulin secretion will normally suppress glucagon secretion.
As blood glucose drops, and insulin secretion decreases, glucagon secretion increases.
IN DIABETES :
- there is an elevation of glucagon levels, despite the hyperglycaemia, that occurs due to the absence of insulin (T1) or insensitivity to insulin (T2) (loss of the normal suppression of glucagon). Increased glucagon contributes to worsening hyperglycaemia.
- the deficiency of insulin fools the body into thinking that there is low glucose because without insulin glucose does not get into the cells => hyperglycemia
- increased glucagon ->increased glucoeogenesis .
- In addition, when glucose is unable to enter muscle/fat cells due to the lack of insulin or insulin resistance, these cells start to breakdown proteins (proteolysis) and fat (lipolysis) to produce energy from alternate sources (otherwise cells are unable to produce energy) - further raising the blood glucose level
- increase in cortisoll and catecholamines ->increase glucogenesis
- . This breakdown of muscle and fat is responsible for the catabolism or weight loss seen in diabetics and occurs as insulin levels decrease.
-Lipolysis produces free fatty acids and generates ketones leading to the subsequent ketoacidosis
-> osmosis diuresis,polyuria,polydipsia,increased urogenital infections ,dehydration (volume depletion) and hypovolaemia, and electrolyte disturbances.
what is HBA1c? what is it’s significance in DM?
HBA1C: Glycated haemoglobin
Haemoglobin covalently bound to glucose cannot separate. When high concentrations of glucose in plasma, a greater proportion of haemoglobin is bound to glucose.
Higher HbA1C % indicates more haemoglobin bound to glucose (therefore a surrogate of higher plasma glucose concentrations).
Glycated haemoglobin is removed as RBC are destroyed as per their normal life cycle of 90 - 120 days
It tell us the three-month average plasma glucose concentration in a patient and can be used as a diagnostic test, and as assessment of glycaemic control in people with diabetes.
what is the normal glucose level?( fasting plasma glucose,2 hour 75g OGTT and HbA1c)
fasting = <5.6 mmol/L
OGTT<7.8 mmol/L
HbA1C= <6 %
How is diabetes diagnosed ?
GLUCOSE LEVELS :
- fasting glucose =>/= 7 mmol/L
- Random plasma Glucose - >/=11.1 mmol/L
-OGTT- >/= 11.1 mmol/L
-HbA1c->/=6.5
1.If symptomatic (polyuria, polydipsia, blurred vision, weight loss, fatigue, recurrent infections): any one of these results on a single occasion.
2. If asymptomatic: any one of the test results on 2 separate days within a 2-week period
3.Fasting plasma glucose performed at least 8 – 10 hours after last meal.
name the 2 pre-diabetic conditions and how are they diagnosed
Impaired fasting glucose is when 2 consecutive tests performed on different days confirm fasting plasma glucose of 6.1 – 6.9 (in the absence of impaired glucose tolerance or diabetes by other tests)
Impaired glucose tolerance is present when 2 consecutive tests performed on different days confirm the 2-hour post load plasma glucoses is 7.8 to 11.0 mmol/L (in absence of diabetes by any other test.)
what is the management of the prediabetic conditions ?
- This are are categories of intermediate hyperglycaemia that identify individuals at risk of diabetes and are considered modifiable risk factors for the development of diabetes.
- Management includes weight loss, diet modification, increase physical activity.
BUT - > Consider metformin therapy in those with worsening FPG or 2-h PG after 6 months of lifestyle intervention (especially if < 60 years old, history of gestational diabetes, BMI > 35, metabolic syndrome)
what is Gestational diabetes ? and how and why is it’s diagnosis different from DM?
Any degree of glucose intolerance with onset or first recognition during pregnancy that is not clearly overt diabetes, with resolution post-delivery.
DIAGNOSIS:
Much lower diagnostic cut-offs for gestational diabetes (FPG 5.1 – 6.9; 2-hour PG 8.5 – 11) and stricter treatment targets
-Typically managed with diet and early use of insulin, but metformin and glibenclamide also used
WHY :
because hyperglycaemia is dangerous to mom and baby (preeclampsia, preterm delivery, polyhydramnios, miscarriage, still birth congenital abnormalities, macrosomia with associated complications, hypoglycaemia post-delivery in infant).
list diabetogenic drugs
-Glucocorticoids
-Thiazide diuretics
-Atypical antipsychotics
-Antiretroviral therapy (protease inhibitors)
compare T1 &T2 diabetes in terms of epidermiology ,heredity,pathogenesis ,clinical presentation and Biochemistry
TYPE 1 : Autoimmune destruction of beta cells with absolute deficiency of insulin. (islet cell autoantibodies can be detected)
- in younger, leaner patients.Increased in those of Northern European ancestry .
-Associated intrinsic genetic factors or extrinsic factors such as viruses, chemical toxins may act as triggers.
Develops abruptly during childhood/adolescence and usually presents with polydipsia/polyphagia/polyuria.
Ketoacidosis is more likely to occur in type 1 than type 2.
Lifelong exogenous insulin required.
Oral hypoglycaemic agents are ineffective as they require some residual functioning beta cells. - Disappearance of C-peptide( During the formation of insulin, the precursor, proinsulin is cleaved into insulin and C-peptide.
In type 1 diabetics, C-peptide will eventual completely disappear as no insulin is produced, so no C-peptide is cleaved)
TYPE2 : Combination of decreased insulin secretion and insulin resistance
- Type 2 usually in older and overweight patients. However, not always case.
- Type 2 DM more gradual onset, may not present with overt symptoms.
Usually, overweight patients older than 35 years.
- Oral hypoglycaemic agents decrease plasma glucose levels, improve insulin resistance, and reduce long-term complications. Many patients will go on to need insulin therapy
-C-peptide will remain measurable.
Explain T2 diabetes and insulin resistance using the Starling curve of the pancrease
- Before diabetes is diagnosed, patients, often obese, have hyperinsulinemia caused by excess dietary carbohydrates which leads to insulin resistance
- Insulin resistance is considered a pathological condition in which cells fail to respond normally to the hormone insulin.
It occurs because of chronic hyperinsulinemia with subsequent insulin receptor down-regulation, leading to defects in insulin binding and post-receptor insulin signalling pathways
-Constant exposure of cells to high levels of insulin leads to insulin resistance – cells become less sensitive to the action of insulin - if not reversed, eventually prolonged periods of hyperinsulinemia cause the pancreas to “burn out” and fail to produce enough insulin to meet demands – relative insulin deficiency.
Resultant hyperglycaemia is also toxic to beta-cells and can progress to complete insulin deficiency.
-This hypersecretion of insulin, which peaks and then declines, is known as the Starling curve of the pancreas
what is meant by metabolic syndrome ?
Metabolic syndrome: a clustering of at least three of the five following 5 medical conditions:
- central obesity
- hypertension
- hyperglycaemia
- raised serum triglycerides
- low serum HDL
Metabolic syndrome is associated with the risk of developing cardiovascular disease, and type 2 diabetes.
what is the mainn feture of metabolic syndrome , core metabolic abnormality and what are the risk factors ?
RISK FACTORS:
diet (particularly sugar-sweetened beverage consumption), genetics, aging, sedentary behaviour or low physical activity, disrupted chronobiology/sleep, mood disorders/psychotropic medication use, and excessive alcohol use. Stress can also be a contributing factor - chronic stress leads to HPA-axis dysfunction, with raised cortisol, hyperglycaemia and hyperinsulinemia.
KEY FEATURE :
visceral/ectopic fat (Central obesity)-> may both result from and contribute to insulin resistance.
CORE METABOLIC ABNORMALITY :
insulin resistance
Markers of systemic inflammation, including C-reactive protein, are often increased.
