Metabolic Integration Of Diabetes Mellitus Flashcards
major diabetes mellitus classifications
Type 1 = autoimmune destruction of B-cells in the pancreas which results in little-no insulin being produced
Type 2 = progressive loss of B-cell insulin secretion due to insulin resistance on peripheral tissues
Gestational = diabetes in the 2nd/3rd trimester of pregnancy that was not seen prior to gestation
Pre-diabetic = higher than normal glucose but not quite diabetes
Normal, prediabetic and diabetic glucose levels
Normal:
- A1c = <5.7
- fasting plasma glucose (FPG) = 99 or below
- plasma glucose 2hr post OGTT = 139 or below
Prediabetic
- A1c = 5.7-6.4
- fasting plasma glucose (FPG) = 100-125
- plasma glucose 2h post OGTT = 140-199
Diabetic
- A1C = 6.5 and above
- fasting plasma glucose (FPG)= 126 and above
- plasma glucose 2h post OGTT = 200 or higher
- random plasma glucose at anytime = 200 or higher
Diabetes mellitus type 1
2 subtypes
1) immune-mediated
- 5-10% of all diabetes
- due to autoimmune destruction of B-cells
- contain islet cell auto-Abs in blood
2) Idiopathic
- less than 0.5% of cases
- no known cause
- there are non auto-Abs
- patients are exceptionally prone to DKA
Symptoms of diabetes mellitus
Usually onset = childhood
- not always though
Extreme thrust
Extreme polydipsia
Dry mucous membranes/ dehydration
General fatigue
Extreme hunger/eating w/ weight loss
may show metabolic acidosis
Why does polydipsia and polyuria occur with diabetes?
Causes when blood glucose is above 180mg/dl
- at this point the SGLT2 (PCT) and SGLT1 (CD) 1transporters become saturated in the renal tubule and results in glucose being spilled into the urine
High levels of glucose in the urine causes osmotic diuresis which brings water into the renal tubule producing polyuria
Polyuria results in increases osmolaritiy in the blood which results in dehydration and polydipsia from baroreceptors
SGLT2 = high capacity, low affinity
SGLT1 = low capacity, high affinity
How does diabetes cause polyphagia?
All stems from lack of insulin
No insulin results in a lack of hypothalamic control of appetite and leads to increased food intake
- insulin induces afferent satiety and adiposity signals which trigger efferent signals that decreases appetitive and increase energy expenditure
Also results in fatigue and weight loss due to inability of restoring muscle glycogen stores and ongoing lipolysis going on respectively in the absence of insulin
How does diabetes result in ketonemia and hyperlipidemia?
Ketonemia = Lack of insulin results in over stimulated production of HMG CoA synthase which produces excess protein down of fatty acids to ketone bodies
Hyperlipidemia = accumulation of fatty acids results in excess chylomicrons and VLDL to accumulate in blood since insulin is required to uptake this
How does ketonemia cause ketoacidosis?
the carboxyl group of the ketone body has a pKa of 4 which in the blood, losses a proton (H+)
- these protons are usually not bad in normal levels of ketone bodies (<3 mg/dl), however in extreme excess like in ketonemia (>90mg/dl), this excess of protons results in metabolic acidosis
- *it is further exacerbated by the osmotic diuresis and dehydration since the H+ ions now have a higher overall concentration since water is lost (this is diabetic ketoacidosis)**
- the frequent symptom of DKA is a fruity odor on breath due to increased acetone (ketone bodies)
Hypoglycemia in diabetic type 1patients
- *this is the most common complication in insulin therapy for diabetic patients**
- this is because they develop a deficiency of glucagon secretion as well (autoimmune destruction) and rely solely on epinephrine to prevent hypoglycemia.
- this occurs within 4 years of diagnosis usually
**however as the disease further progresses, the ability to secrete epinephrine due to diabetic autonomic neuropathy (damage to the autonomic nerves) become evident, leading to potential severe glycemic
Results in seizures and coma if it gets too severe
Diabetes type 2 pathophysiology
Develops from insulin resistance in peripheral tissues
- decreases in glucose uptake by insulin sensitive GLUT4 receptors in peripheral tissues
- follows the two hit hypothesis (1 is the insulin resistance itself, but is asymptomatic until the second hit occurs (which is the actual insulin insufficiency from B-cells)).
- causes of the first hit: diseases, overweight/physical inactivity, steroid use, gaining, sleep problems, cigarette smoking, etc.
- causes of second hit: genetics, glucose or fatty acid toxicity
Why do you need the insulin insufficiency in combo with insulin resistance to develop diabetes?
Initially when insulin resistance occurs, the patient is hyperinsulinemic which can compensate for this at least enough to prevent major symptoms
However chronic forms of this eventually lead to B-cell dysfunction and decline in insulin production and worsening hyperglycemia to the point where there are now symptoms
Microvascular and macro vascular complications of diabetes
Micro vascular = retinopathy, nephropathy, myopathy, neuropathy
Macro vascular complications = CV disease, stroke, etc.
Differences between DIabetes type 1 and 2 clincially
Type 1:
- usually childhood onset (not always)
- is abrupt onset
- symptoms are more severe usually
- DKA is common
- hyperlipidemia sometimes is present
- obesity is not common
- is autoimmune based
Type 2:
- usually adulthood onset
- is gradual onset
- symptoms are less severe usually but still present
- DKA is rare*
- hyperlipidemia is present
- obesity is common
- not autoimmune
**both show the 3 P’s (polyuria, polyphagia, polydipsia) both show hyperglycemia and hyperlipidemiaand both are usually related to weight loss*
- also both are genetic with type 2 being more genetic*
- type 1 is HLA mediated also
How does insulin resistance affect metabolism?
Increases adipose lipolysis but decreases FA oxidation
- build up of FAs and LDL/chylomicrons
Increase in hepatic gluconeogenesis And decrease in glucose uptake by muscles and adipose tissues - results in build up of blood glucose
Management of diabetes
Both type 1 and 2 require lifestyle changes
- regular exercise
- diet modifications
- weight reduction
Pharmacology:
- type 1 = insulin injections and monitor for hypoglycemia
- type 2 = multiple different therapies
