Diabetes 2 Flashcards
where is glucose reabsorbed?
90% in SI segments of proximal tubule by SGLT2
10% in distal S2/S3 segments of proximal tubules by SGLT1
what is the capacity and affinity of SGLT1?
where is it located?
low capacity
high affinity
distal end of the proximal tubule
what is the capacity and affinity of SGLT2?
where is it located?
high capacity
low affinity
proximal tubule
Epidemiological studies and nutritional experiments have shown that excessive consumption of fructose is closely linked with
…metabolic abnormalities including dyslipidemia, obesity, diabetes, and cardiovascular disease.
compare the site, renal location, affinity for glucose, capacity fro flucose transport and percent of renal glucose reabsorption of SGLT1 and SGLT2
SGLT1: motly small intesting, some kidny and heart, late proximal straight tubule (S3), High (km=0.4mM) affinity, low capcity, 10%
SGLT2: almost axclusively kidney, early proximal convoluted tubule (S1), low (Km=2mM)affinity, high capcity, 90%
what is Phlorizin?
Phlorizin has played a vital role in elucidating the mechanism of renal glucose reabsorption and the role of hyperglycaemia in diabetes.
This agent was first isolated in 1835 by French chemists from the root bark of the apple tree.
Subsequently, it found to be a potent but relatively non-selective inhibitor of both SGLT2 and SGLT1.
what is Dapagliflozin
Dapagliflozin is a selective SGLT2 inhibitor with 1000x selectivity over SGLT1.
The FDA approved dapagliflozin on January 8, 2014 for glycemic control, along with diet and exercise, in adults with type 2 diabetes.
The SGLT2 inhibitors in human clinical trials have good efficacy, but they do not inhibit >30–50% of the filtered glucose load.
canagliflozin
Inhibiting SGLT2 in the kidney provides many advantages, what are they
5
- glucose is cleared from the circulation without the need for insulin, thereby lowering the demands on pancreatic β-cells;
- glucose excretion decreases as blood glucose levels decrease, thereby limiting the risk of severe hypoglycemia;
- urinary glucose excretion (UGE) may lower blood pressure; and
- UGE may lead to weight loss.
- Novel mechanism is compatible with other glucose-lowering therapies.
All these advantages were observed in recent studies of SGLT2 inhibitors.
what are the side effects of SGLT2 inhibitors?
Repeated urinary tract infections
Genital infections
Increased haematocrit
Decreased blood pressure
Possible increase in bladder cancer
what is metformin
Originates from the French lilac, a plant used in folk medicine for several centuries.
First described in 1922, approved by the British National Formulary in 1958 but only approved in the USA in 1995 (worries of cardiovacular events as a result of the withdrawal in 1977 of phenformin).
Metformin was believed to make cells more sensitive to insulin.
Prescribed in combination with many of the other diabetic drugs
what effects does metformin have
Metformin is the only antidiabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes.
It helps reduce LDL cholesterol and triglyceride levels.
It is not associated with weight gain.
Low risk of hypoglycemia.
Metformin works by suppressing glucose production by the liver.
what is the intial drug treatment recommended for type 2 diabetics
metformin
what are the benefits to metformin
It is cheap, proven to be safe and, therefore, the most widely used diabetes drug in the world.
Many studies have shown that patients on metformin have a reduced incidence of cancer.
Metformin reduced hyperglycemia mainly through the suppression of gluconeogenesis in the liver.
broadly how does metformin work
Metformin decreases liver glycogenolysis and gluconeogenesis (probable primary effect) and increases glucose uptake in muscle.
decreases conversion of glycogen to glucose in liver cells (glycogenolysis) and increases the conversion of glucose to glycogen in muscle cells (Glycogenesis)
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.
Action via altered metabolic state of hepatic cells
what is Amylin?
Amylin, or Islet Amyloid PolyPeptide (IAPP), is a 37-residue peptide hormone.
It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1.
Like insulin, it is synthesised as a larger protein that is cleaved (including signal sequence) to produce the mature active peptide.
Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
