Diabetes (MEDCHEM)

what is diabetes characterized by?

hyperglycemia

describe type 1 diabetes:

• b-cells are damaged

• pancreas can no longer produce insulin

describe type 2 diabetes:

• aka non- insulin-dependent diabetes mellitus [NIDDM] or adult onset diabetes

• patients develop insulin resistance

where and when is insulin secreted?

secreted by b-cells in the Langerhans islets of the pancreas when blood glucose concentration rises

how does insulin reduce blood glucose levels?

• either by inhibiting hepatic glucose production (glycogenolysis and gluconeogenesis)

• or by increasing glucose uptake into the liver, muscle, and fat tissue

how does glucagon reduce blood glucose levels?

secreted by pancreatic a-cells in response to low concentrations of glucose

How does glucagon increase blood glucose levels?

It acts principally on the liver and antagonizes the effects of insulin by increasing glycogenolysis and gluconeogenesis

how is glucose transported across membranes?

by glucose transporters (GTs)

what are glucose transporters (GTs)?

a family of membrane-bound glycoproteins: sodium-glucose cotransporters (SGLT) and facilitative glucose transporters (GLUTS)

Where is the SGLT1-type transporter located? How does it transport glucose?

• in the absorptive epithelial cells of the intestines

• transports glucose against its concentration gradient

what is insulin composed of?

two polypeptide chains (A and B) with 51 amino acids total.

how many AA does chain A contain?

21

how many AA does chain B contain?

30

how are chains A and B linked together?

by two disulfide bridges (ACys7-BCys7) and (ACys20-BCys19)

where is the third intramolecular disulfide bridge found?

in chain A (Cys6-Cys11)

what do the disulfide bridges of insulin provide?

chemical stability

where is insulin synthesized?

in the b-cells of the pancreas from preproinsulin, a 110 amino acid chain

What is preproinsulin?

110 AA chain, precursor of proinsulin

what is proinsulin?

precursor of insulin, 86 AA chain

what happens to proinsulin once formed?

• loses four basic amino acids (ArgB31, ArgB32, LysA64, ArgA65)

• releases a 31-amino acid connector C-chain

what 4 basic AA does proinsulin lose in the golgi apparatus?

ArgB31, ArgB32, LysA64, ArgA65

how does proinsulin lose its 31-AA connector C-chain?

by the action of prohormone convertases PC 1 and 2

what enzymes catalyze the cleavage of a dipeptide segments to produce insulin?

prohormone convertases (PC) 1 and 2

how are human insulin and insulin analogues formed?

by recombinant DNA techniques

what type of insulin is the only type able to interact with insulin receptors?

the insulin monomer

what is a longer-acting and more stable form of insulin?

protamine zinc insulin

why do insulin molecules have a tendency to form dimers in solution?

due to the formation of hydrogen-bonding between the C-terminus of B chains

what happens to insulin dimers in the presence of zinc ions?

they associate into hexamers

T or F: Monomers and dimers readily diffuse into blood, whereas hexamers diffuse poorly.

true

active form of insulin

monomer

storage form of insulin

hexamer

what happens to insulin when stored at 4°C?

• deamidation of the Asn at A21 occurs at a rate of 1-2% per month

• Asn undergoes cyclization to the anhydride which reacts with water leading to deamidation

what happens to insulin when stored at 25°C?

the inactive deamidated derivative constitutes 90% of the total protein after 6 months.

what happens to insulin when stored at neutral pH?

deamidation reaction producing the aspartate- and isoaspartate containing insulins which are equiactive with native insulin

describe the solubility of insulin at neutral pH:

insulin at neutral pH has low solubility

how are insulin analogs classified?

according to their rate of onset and duration of action

what do variations in or addition/removal of amino acid residues from the C-terminus of the B chain starting at residue B28 result in?

could influence the rate of onset, duration of action, and rate of dimer formation while not drastically changing the biological activity

what does inhibiting dimer formation result in?

rapidacting insulin

what are the rapid-acting insulins?

insulin lispro, aspart, and glulisine

where do insulin lispro, aspart, and glulisine have changes made?

the amino acid residues in the C-terminus of the B chain

what is the change made in Insulin Lispro?

the B29 Lys is switched with B28 Pro

what is the change made in Insulin Aspart?

the B28 Pro is changed to an Asp

what is the change made in Glulisine?

• B3 Asn is changed to a Lys

• B29 Lys is changed to a Glu

what do the changes made in insulin lispro, aspart, and glulisine result in?

insulin analogues that do not form dimers in solution and dissociate immediately into monomers, producing a very quick onset of action

Pharmacodynamically, Lispro, Aspart, and Glulisine bind as well to insulin receptors as?

human insulin

what is the onset of action and DOA of Lispro, Aspart, and Glulisine?

They have an onset of action within 15 minutes and a duration of 3-4 hours

what type of insulin is regular human insulin? what is its onset of action? what is its DOA?

• short-acting insulin

• It has an onset of action within 30-60 minutes

• has a duration ranging 4-6 hours

what is the onset of action and DOA of NPH?

onset of action of 2-4 hours and duration of 18-26 hours after injection

what was the first long-acting insulin analogue?

insulin glargine

what is the onset of action and DOA of insulin glargine?

• Slow dissolution from the site of injection results in an onset of 1-4 hours

• DOA of 20-24 hours that represents a fairly constant release of insulin glargine over 24 hours

how does insulin glargine differ from regular insulin?

• AsnA21 --> GlyA21

• ArginineB31-ArgB32 is attached to B chain

• more basic --> soluble in acidic formulation, but decreased solubility at physiological pH

• isoelectric point = 7, which increases ppt on SC, and decreases absorption rate

• dissolved slowly, delayed absorption after SC (pH~7) --> long-acting --> once daily administration

how is insulin degludec made?

the removal of B30 Thr, N-acylation of B29 Lys with l-g-Glutamic acid linker that is acylated with hexadecanedioic acid

what is insulin degludec?

an ultra-long-acting insulin that can be administered daily or three times a week

what makes insulin degludec have a long DOA?

(1) the formation of soluble multihexamer assemblies upon SC administration which slowly release monomers

(2) hexadecandioic acid side chain binding to plasma albumin to produce a depot

what is the association of insulin monomers to dimers and larger aggregates is a function of?

pH, ionic strength and protein concentration