what causes metabolic syndrome
- low HDL cholesterol
- visceral obesity
- insulin resistance
- hypertension
- high triglycerides
why is obesity and type 2 diabetes linked
Obese individuals have more adipose tissue which increases the amount of
adipokines that are released.
Adipokines can be inflammatory and therefore initiate insulin resistance in
adipocytes
there can be increased macrophage infiltration of the adipose tissue which will further increase the basal level of adipose inflammation and exacerbate inulin resistance
what is obesity associated with
- it is associated with an increase in the number of free fatty acids in the blood stream
- free fatty acids can increase the synthesis of diacylglycerol and this can cause diacylglycerol induced activation of protein kinase C isoforms
- PKC can phosphorylate serine and threonine residues on IRS which prevents the phosphorylation of tyrosine on the IRS, AKT is therefore not produced
what is the difference between visceral fat and subcutaneous fat
- Visceral fat - this is a high degree of fatty tissue within the abdomen
- visceral adipose cells also produce signifiant amounts of pro inflammatory cytokines such as TNF-a and IL-1 and IL-6
- also linked to NAFLD
- Subcutaneous fat - distinct from subcutaneous adiposity or fat between the skin and the muscle wall especially elsewhere on the body such as the hips or thighs
what do visceral adipose cells produce
Unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory cytokinessuch as tumour necrosis factor-alpha andinterleukins -1 and -6, etc.
what do pro inflammatory cytokines do
these proinflammatory cytokines disrupt normal insulin action in fat and muscle cells, and may be a major factor in causing the whole-body insulin resistance observed in patients with visceral adiposity.
what is visceral adiposity also linked to
Visceral adiposity is related to an accumulation of fat in the liver, a condition known asnon-alcoholic fatty liver disease(NAFLD).
what is the result of NALFD
The result of NAFLD is an excessive release of free fatty acids into the bloodstream (due to increased lipolysis), and an increase in hepatic glycogenolysis and hepatic glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood oftype 2 diabetes.
what things happen in order to get type 2 diabetes with obesity
1) increased production of adipokines/cytokines, including tumor necrosis factor-α, resistin, and retinol-binding protein 4, that contribute to insulin resistance as well as reduced levels of adiponectin
2) ectopic fat deposition, particularly in the liver and perhaps also in skeletal muscle, and the dysmetabolic sequelae
how does metformin work
This is a biguanide.
- Decreases hepatic gluconeogenesis primarily by a transient reduction in activity of the mitochondrial respiratory-chain complex 1.
- Metformin also increases glucose uptake in skeletal muscle via GLUT4.
- increases GLP-1 reducing blood glucose in muscles
- only effective if you have pancreatic B cells
how does gliclazide work
This is a type of sulfonylurea which attaches to the ATP dependent potassium pump and reduces potassium outflow in beta pancreatic cells. This depolarises cell membrane and activates voltage dependent calcium channels which allows for vesicle fusion and release.
how does pioglitazone work
- This is a type of thiazolidinedione (TZD) which is used to increase sensitivity to insulin.
- TZDs act by activatingPPARs(peroxisome proliferator-activated receptors), a group ofnuclear receptors, with greatest agonist specificity forPPAR-gamma, PPARG. The endogenousligandsfor these receptors are (FFAs).
- make you gain weight - our person is trying to loose weight
how does sitagliptin work
– This will competitively inhibit the enzyme dipeptidyl peptidase 4 which breaks down GLP-1 and GIP – the gastrointestinal hormones released after eating which increase the release of insulin and also induce satiety.
why does he need insulin injections
The insulin resistance will result in compensation by the pancreas which will increase the beta cell mass.
However, this hyperinsulinemia will further exacerbate the resistance (desensitisation).
Eventually, the beta cells undergo decompensation as the cells are unable to maintain their secretion of insulin.
The beta cells begin to die. It is the loss of functional insulin producing beta cells which necessitates insulin injections
what does HbA1c measure
Hba1c – a measure of haemoglobin glycosylation
When blood glucose concentration is high, the glucose will covalently bond with the protein haemoglobin
what is HbA1c a measure of
HbA1Cis a measure of your average blood glucoselevelover3 months. YourHbA1C target should be under 48mmol/mol (6.5% of total RBC).
what is acanthuses nigricans
Dry, rough, thick and velvety patches on the skin, especially near skin folds such as the neck,armpit, around the groin and sometimes in other skin folds
what is acanthuses nigricans a sign of
Is a clinical sign of hyperinsulinemia – the insulin will bind to and stimulate insulin receptors and growth-factor 1 receptors on keratinocytes and dermal fibroblasts
why does Addisons disease happen
This occurs becausemelanocyte stimulation hormone (MSH) and ACTH share the same precursor molecule, pro-opiomelancortin (POMC).
After production in theanterior pit. gland, POMC gets cleaved into gamma-MSH, ACTH, andbeta ipotropin.
The subunit ACTH undergoes further cleavage to produce alpha-MSH, the most important MSH for skin pigmentation
what is nocutira
- urination at night
how is glucose reabsorbed
- Once inside the epithelial cells, glucose re-enters the bloodstream through facilitated diffusion throughGLUT2transporters.
what is PPARG
PEROXISOME PROLIFERATOR – ACTIVATED RECEPTOR GAMMA (PPARG
what does PPARG do
A nuclear receptor
A transcription factor
Stimulates adipocyte differentiation – stimulating lipogenesis and lipid / FFA uptake - greater risk of type 2 diabetes due to obesity
what does GKRP stand for
GLUCOKINASE REGULATORY PROTEIN
