Diabetes Mellitus Flashcards
Diabetes
Group of metabolic diseases in which there are high blood sugar levels over a prolonged period
Insulin structure
Protein hormone consisting in 2 chains linked together by disulphide bridges forming a dimer.
Insulin production
In the islets of langherans (endocrine pancreas), beta cells.
Preproinsulin -> proinsulin -> insulin + C-peptide
Insulin secretion
These cells release insulin when the concentration of glucose in blood is raised. Glucose enters the β cell through GLUT2, this transporter is found only in the pancreas and liver, it has a high transport capacity and allows fast equilibration of extracellular-intracellular glucose. Once in the cell, glucose is phosphorylated by Glucokinase, rather than by Hexokinase. GK enzyme is not inhibited by its products, contrarily to HK, giving high rates of reaction . Once phosphorylated glucose is metabolized through the glycolytic pathway. The ATP produce by the process is able to block the outflux of potassium from the KATP channel. (The potassium channel is composed by 4 Kir6.2 and 4 SUR1 peptides).This leads to a cellular depolarization (>-40mV) that opens Ca2+v channels that promote insulin vesicle fusion with the membrane thus the release of the hormone.
Curve of insulin secretion
Biphasic. two phases: the 1st occurs in the first 10’ and has a high peak of secretion, while the 2nd lasts longer and has a lower level of secretion. This profile curve was measured by the administration of a glucose bolus that produces a squared wave of hyperglycemia.
the 1st phase results from rapid insulin vesicle mobilization while the 2nd has a lower peak because requires additional steps of insulin biosynthesis.
The in vivo profile however is not superimposable because sugar absorption is progressive and continuous, meaning that the hyperglycemia pulse is not squared.
Incretins
incretins, as GLPs, are able to boost insulin secretion following a meal. These peptides are produced by the intestine in response to food digestion and prime the pancreas for insulin secretion.
They are rapidly degrated by the enzyme DPP-4.
Insulin degradation
Degraded by liver and proximal tubular cells in the kidney. Half of the insulin secreted from the pancreas is degraded in the liver and never reaches the systemic circulation. For this reason, after release, the concentration of insulin in the portal circulation is much higher than that in the peripheral circulation.
Insulin action
- In the liver, it promotes glucose uptake and glycogen synthesis, lipogenesis and protein synthesis, while simultaneously discouraging the associated catabolic pathways.
- In muscles it stimulates glucose uptake and glycogen synthesis while inhibits the secretion of lactate. It further promotes protein synthesis and fat degradation. - In the adipose tissue insulin promotes glucose uptake while inhibiting the flow of gluconeogenic precursors to liver and stimulates triglyceride formation.
Counterregulatory hormones of insulin secreted during fasting
Glucagon, cortisol, EPI and GH
Diabetes classification
Insulin deficiency, in immune mediated type 1 diabetes, marked by a progressive loss of β cell mass that leads to insulin insufficiency.
Insulin resistance with associated insulin deficiency in monogenic and polygenic type 2 diabetes. As disease (type 2) progresses insulin deficiency may develop. Due to β cell exhaustion following prolonged times of hyperfunctioning.
Insulin receptor activation
Insulin is the prototypical anabolic hormone. The downstream effects of insulin stem from the activation of the insulin TKR. IRS proteins are recruited to the plasma membrane by pleckstrin homology (PH) domain. PTB domains of IRS bind to the phosphorylated residues of the receptor. IRS contain up to 20 potential phosphorylation sites, formin additional docking sites for SH2 domain containing proteins. These pY chains allow response amplification. the downstream activated pathways are the MAPK (Grb2-SOS-ERK), PI3K that activates PKB and the mTOR pathways.
advanced glycation end products
High levels of free glucose lead to the formation of AGEs, i.e. advanced glycation end products, that are sugar modified proteins. These modifications occur spontaneously , without the need of any enzymatic chaperone. One common AGE metabolite is Hb1Ac. Many of these glycated products are involved in inflammatory reactions.
Common diabetes complications
1) retinopathy
2) nephropathy
3) neuropathy
4) Diabetic foot disease
5) macrovascular (CAD, MI, stroke, peripheral arterial disease -> ischemic ulcers)
Goals in the general population (Hb1Ac, glycemia levels)
Fasting glucose: 90-130 mg/dl, postprandial < 180 mg/dl and Hb1Ac < 7.0%. in pregnant women values are further controlled, 60-100 mg/dl, 100-130 mg/dl and < 6.0%.
Sulphonylureas
Aim to increase glucose secretion by acting on the ATPreceptor (SUR1) of the potassium channel in the β-cell. This is the only type of drug for DM2 that is able to induce hypoglycemia.
- The first generation of this drugs are represented by glibenclamide (glyburide). This molecule has a long half life, thus promoting insulin secretion long after meals, increasing the risk for hypoglycemia.
- 2nd gen as glimepiride, but even better gliclazide and glipizide are less competitive agonists of the SUR1 and usually not very active in the absence of ATP, giving a more efficient temporal control of insulin secretion. These drugs are thus safer than glibenclamide.
- Meglitinides are similary to SU but are probably more active on the Kir6.2 channel. These drugs have a shorter half-life and a rapid effect, being thus more safe. Both SU and meglitinides are excreted via kidney, some SU also through bile. Both kinds of drugs are very cheap and often used as 1st line treatments in DM2.
Biguanides
such as metformin, a very safe and cheap drug.
The main effect
- regulation of peripheral insulin sensitivity
- control of hepatic gluconeogenesis
Side effects
- mild GI disturbances
- Vitamin B12 deficiency
- metabolic acidosis when overdosed or in patients with renal impairment
Good point
- No hypoglycemia or weight gain!
- Reduce the risk of CV complications and cancer risk
Pharmacodynamics of this drug is not completely clear, but it appears to be working on mitochondrial proteins especially when inhibiting hepatic gluconeogenesis.
Metformin has become the most prescribed agent for DM2 worldwide.
GIP
Glucose-dependent insulinotropic peptide
- Encoded by gip gene
- Produced and released by enteroendocrine cells (K cells) in the proximal part of the intestine in response to nutrients (fat or carbohydrate) detection.
- In DM type 2 GIP no longer modulates insulin secretion
GLP-1
Glucagon like peptide
- Derive from the same gene as glucagon but it has an insulinotropic action
- Produced by enteroendocreine L cells
- Induces an increased release of insulin by increasing intracellular calcium
Exenatide may slow absorption of analgesics.
GLP-1 receptors agonists
- Exenatide (-tide), Liraglutide, Dulaglutide, Lixisenatide
The stimulation of GLP-1 receptors promotes a slower gastric emptying , decreases insulin resistance, promotes insulin secretion , lowers BP and reduces CV mortality.
GLP1Rs are differentially expressed and cannot be found in many tissues.
GLP1 also have strong anti-inflammatory properties.
GLP1RAs are administered subcutaneously but semaglutide was proven to be efficacious orally when associated to SNAC. SNAC is salcaprozate sodium, a derivative of salicylic acid, it works as chaperone promoting the permeation of the drug as a carrier. It basically increases stomach pH and promotes transcellular transport. This approach could be considered for oral administration of insulin.
DPP4i
work on the same axis of GLP1RAs by inhibiting the cleavage of endogenous GLP1, increasing its half-life. These drugs are safe from CV profile and are given subcutaneously (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin).
Low risk of hypoglycemia, no weight gain, against beta cells burnout, can be used in patients with kidney failure.
Alfa-glucosidase inhibitors
Alfa-glucosidase inhibitors act in the gut, they block saccharide cleavage inhibiting the absorption of simple sugars and carbs in general. These drugs are not commonly used, they are poorly tolerated, given the high GI discomfort. These are Acarbose, Miglitol and Voglibose.
May decrease digoxin absorption and warfarin effect.
SGLT2i
SGLT2i block renal reabsorption of glucose in the proximal tubules. These drugs are known as glycosurics and include canagliflozin, dapagliflozin and empagliflozin. They promote glycosuria and natriuresis. These drugs give CV protection, control diabetes and are protective for renal diseases . These drugs may give severe hypoglycemia especially when paired to insulin or SU.
They should not be employed in patients with an eGFR < 60 ml/min!
increased risk of genital infections
Whipple triad
Helps to confirm the diagnosis of hypoglycemia. Historically, it has been described as diagnostic criteria indicative of an insulinoma.
- Low plasma glucose concentration
- Signs or symptoms consistent with hypoglycemia
- Relief of symptoms when plasma glucose increases after treatment
Signs and symptoms of hypoglycemia
Neurogenic/autonomic
- Increased sympathetic activity: tremor, pallor, anxiety, tachycardia, sweating, and palpitations
- Increased parasympathetic activity: hunger, paresthesias, nausea, and vomiting
Neuroglycopenic
- Agitation, confusion, behavioral changes
- Fatigue
- Seizure, focal neurological signs
- Somnolence → obtundation → stupor → coma
