Treatment of diabetes

insulin therapy: injections, pumps

perspectives:

• insulin stray, other hormones

• graft of islets

• immunotherapy

—> Insulin therapy only way to treat T1D

low-fat diet (unsaturated)

exercise

oral drugs

bariatric surgery (when associated with severe/morbid obesity)

—> increase sensitivity to insulin

several types of insulin working at different speeds (onset) and their effects last a different length of time (duration)

• rapid-acting

• short-acting (regular)

• intermediate-acting

• long-acting

needle and syringe

pen

pump

inhaler: breathing powdered insulin but lots of secondary effects in the nose

way to measure and collect glucose data using a scanner on a sensor

sensor measures the level of glucose in the interstitial fluid

sensor records & stores all measured data up to 8 hours

to obtain the glucose level, the reader must pass over the sensor

automated insulin delivery (closed loop)

glucose sensor -> algorithm controller -> insulin pump

depending on glycemia injection of insulin directly adapted

information sent on the smartphone -> calculates automatically quantity of insulin to infuse

good results & greatly simplified diabetic life but delay of answer & expensive

for T1D patients unable to secrete enough insulin & with kidney complications

double graft pancreas/kidney (graft survival improved) but < 150 grafts/year in France

need to inhibit the secretion of digestive enzymes

transplantation complicated due to exogen & endogen function

good results: 90% of survival graft after 1 year & 70% after 5 years

main advantage: real cure for diabetes -> no more injection in less than 1 year in 76%, no hypoglycemia

BUT: numerous complications post-surgery, slight mortality risk & lifetime immunosuppressive treatment

isolate ß-cell & inject them in portal vein -> migrate in liver -> again functional

reserved for instable T1D patients with a prognosis for survival involved

experimental procedure until 2020, needs 1-3 donors (only done by 4 groups in France)

transplantation has to be done several times to reach good BCM

50% became insulin-independent in 3 years following the transplantation

less complicated than a pancreas-kidney transplant

BUT: 2-3 donors for 1 patient & immunosuppressive treatment

-> Research on the production of ß-islets in the laboratory

Graft function persisted in 82% & 78% of cases after 5 & 10 years -> associated with improved glucose control, reduced need for exogenous insulin & decrease of severe hypoglycemic events

interesting in the future

human pluripotent stem cells & patient-derived iPSC

basis for potentially unlimited numbers of replacement cells

ß-cell transplant is also xenogenic possible

microspheres capsules: protection of the islets, release of insulin

most advances in Allo islets & artificial pancreas

—> diet & physical activity

—> One oral anti-diabetic agent (OAD)

—> combination of several OAD

—> Insulin + OAD

—> Insulin

Metformin first drug is given to all with functional kidney

if not sufficiently adapted to patient history

reduction in the incidence of T2D with lifestyle intervention or metformin

metformin most effective drug

high impact due to changed lifestyle (diet & exercise)

insulin sensitizers & insulin secretion stimulators

SGLT2 inhibitors: inhibit the reabsorption of glucose in the kidney

Glitazones: decrease insulin resistance (not authorized due to side effects)

Metformin: decrease hepatic glucose production (decrease insulin resistance)

Sulfonylureas: increased secretion of insulin

GLP1-R agonist: stimulates insulin secretion

decrease insulin resistance -> ameliorates insulin action in muscles, adipose tissue & the liver

consequently induces a decrease in glycemia after a meal

main target: liver (uptake unknown but probably by endocytosis)

inhibits complex I of the mitochondrial respiratory chain (variation of energy ratios) -> increased ß-oxidation

depolarization of hepatocyte membrane (modifications of Cl-movement

could be able to bind protein sites instead of bivalent cations (Ca2+ increase in mitochondria)

activation of cellular respiration at a low dose

activates AMP-activated protein kinase AMPK ->stimulates energy depletion

improved insulin receptor function & glucose transport, reduced FA synthesis

improved insulin sensitivity & inhibition of gluconeogenic pathways

the opposite effect of glucagon -> inhibits the production of glucose

muscle & liver

muscle: increases FA oxidation & glucose uptake

liver: increases FA oxidation, decreases cholesterol synthesis & lipogenesis

-> induces translocation of GLUT4 (but from another pool than via insulin)

increase: muscle glucose transport & liver insulin sensitivity

decrease: hepatic steatosis

—> decreased plasma glucose & plasma triglycerides

induce normoglycemia rather than hypoglycemia -> live normally with diabetes

inhibit neoglucogenesis & aerobic glycolysis, stimulate anaerobic glycolysis

reduce intestinal resorption of glucose, galactose, AA

inhibit lipolysis & FA production (lipogenesis)

overtime increased sensitivity & secretion of insulin

positive action on vessels (endothelial function)

less ROS production

less arthero sclerosis& decreased cardiovascular risk

strengthens the efficiency of biguanides

decrease cardiovascular events/ infarcts/ mortality linked to diabetes & also total mortality

-> Decrease risk of complications linked to T2D

used in the first intention in diabetes

increase secretion of insulin

all contain a central S-phenylsulfonylurea structure (lots of drugs with different modifications)

bacteriostatic action (used before the discovery of antibiotics) & some derivatives stimulate insulin production

oldest & most used medication for the treatment of T2D

pancreas

oblige the pancreas to produce more insulin at the same blood glucose level

potentization of the glucose-induced insulin secretion effect

thermostat function of the pancreas is preserved -> quantity of produced insulin still glycemia dependent

K+ ATP-dependent channel

binds sulfonyl uranyl receptor

ATP binding (Kir6 TMDO domain) inhibits K+ channel -> depolarization

the drug binds other domain (SUR) -> potentization of closure of the channel

but still hyperglycemia needed to work

depolarization increases Ca2+ -> increased glucose secretion

increased insulin secretion leads to inversion of the vicious cycle -> impacts glucose resistance

used in combination with metformin

act on the pancreas & induce insulin secretion

oblige the pancreas to produce insulin independently of glycemia increase

acts within 15 min after absorption before a meal -> effect lasts ust during digestion & dose-dependent

->acts only for the meal before which it was taken

tolerance excellent, action fast & short diminishing the risk of hypoglycemia

acts directly on the channel & closes it

not dependent on ATP level (even in hypoglycemia closed)

tight control needed

Incretin analogs agonist of GLP-1 receptors but oral uptake is not possible

main site of action: pancreas

Major effects: increased insulin secretion & decreased glucagon secretion (both glucose-dependent)

slows down gastric emptying -> increased satiety

decreases the appetite

increase: insulin secretion & ß-cell proliferation

decrease glucagon secretion, ß-cell apoptosis & ER stress

—> increased insulin sensitivity

binds GLP-1R -> ATP to cAMP -> PKA↑ —> Ca2+↑ (from ER) —> insulin secretion

decreases glycemia after meals

inversion of the vicious circle -> decrease of insulin resistance in the long term

inhibitor of the endopeptidase DPP-4 (dipeptidyl proteinase 4) -> responsible for GLP-1 degradation

orally administered with a significant effect on glucose tolerance & lasting improvement of HbA1c

inhibits GLP-1 degradation

↑ active GLP-1/GIP concentration —> ↑insulin secretion

↓ glucagon secretion

pleiotropic mechanism of DPP-4 inhibition

DPP-4 inhibition in peripheral plasma preventing inactivation of circulating GLP-1

↑ insulin secretion & decreased glucagon secretion

in the gut: ↑ GUT & portal GLP-1 -> ↑ autonomic nerve activity & decreased hepatic glucose production

in the pancreatic islets: ↑ insulin secretion & decreased glucagon secretion/islet inflammation

also prevents the inactivation of other peptides

advantage: oral availability (GLP-1R agonist injected)

but in contrast to GLP-1R agonist weight neutral (GLP1R agonist >85% lose weight)

Gliflozine works on the proximal convoluted tubule in the kidney -> increases removal of glucose

Na+/glucose cotransporter that normally leads to reabsorption of glucose -> with inhibition more in urine

glucose reabsorption in the first part of the tubule to 80% SGLT-2 dependent

effects on the body

• decreased plasma glucose

• increased insulin sensitivity

but has no clinical advantages compared to existing treatments->no reimbursement

might have an impact on cardiovascular disease mortality

different onset & duration

short-acting most common

not indicated in the first intention nor monotherapy

only in obese patients

indicated in T2D treatment associated with metformin or sulfonylurea when control of glycemia is insufficient

origin clofibrate has anti-lipidemic activity & slightly anti-hyperglycemic

synthesis of several analogs

mainly the adipose tissue

but also muscle & liver (pancreas indirect)

differentiation of new adipocytes metabolically active via PPARγ -> more sensitive to insulin than existing adipocytes

->facilitate glucose uptake by adipose tissue inducing a decrease of glycemia after a meal

->facilitate FA uptake by adipose tissue, decreasing circulating FFA in the blood

->induces redistribution of lipids within the body with a decrease in visceral fat (facilitates vascular complications) and an increase in subcutaneous abdominal fat (no facilitation of vascular complications)

->weight gain of 1-4 kg observed in relation with the treatment

ligand of PPARγ (peroxisome proliferator-activated receptor γ)

-> Increase gene expression in adipocytes

-> Indirect effect in muscle & liver

significant increase in myocardial infarction risk ->increase in mortality / CVD

heart failure risk

only allowed in the US if nothing else works

high side effects

look at molecules activating PPARγ & only regulate 1 cluster of genes

find a cluster with beneficial effects & no adverse effects

CDK5 phosphorylation of PPARγ induces a transcriptional program that is distinct from that of unphosphorylated PPARγ

SGLT2i have demonstrated decreased cardiovascular risk ->increased prescription

DPP4i leads in contrast to cardiovascular risk

salicylates to reduce the inflammation

Antioxidants

insulin mimetics

ceramide inhibitors

but drug development long process (safety->efficacy (from small to large to long-term side-effects)) & loses patent after 20 years

1. based exclusively on gastric restriction (decreased size of the stomach): gastric ring or longitudinal gastrectomy

2. gastric bypass ->decrease of ingested food quantity (decreased volume of the stomach) & malabsorption in reducing the length of the small intestine receiving food & biliopancreatic fluids

common in the US -> good long-term results with important & stable loss of weight (success rate at 10 years 80%)

but heavier for the body than a ring

in France bariatric surgery in adults under restricted conditions: BMI >40 or >35+comorbidity susceptible to be improved

->hypertension, severe respiratory troubles, T2D, NASH

in the second intention after the failure of medical treatment in combination with nutritional/dietetic/psychotherapeutic well-conduct for 6-12 month

an important issue in the follow-up of patients -> should therapeutic management be different after surgery?

->stomach also degrades drugs -> adapt dosage to metabolization

spontanoues mutation ‘fatty‘

no regulation of food intake->eat to much->obese

mutation on the hypothalamic leptin receptor, high level of plasma leptin -> leptin resistance

hyperphagia, storage in adipocytes: hyperplasia & hypertrophy ->obesity (14 weeks old 40% of BW = fat)

dyslipidemia, hyperinsulinemia, glucose intolerance

->insulin resistance

Zucker diabetic fatty

diabetic with a high lipid diet

mimic the human adult onset of T2D & related complications

develop insulin resistance

shortened leptin receptor

ob/ob mice

leptin deficient

obesity, hyperinsulinemia, hyperglycemia at 4 weeks

db/db mice insulin resistant

fasting hyperglycemia at 8 weeks-old

chemical induction leads to the destruction of ß-cells (enter via GLUT2 & induce apoptosis)

spontaneous autoimmune: NOD mice

genetically induced: AKITA mice

virally induced

tissue specific

cre recombinase expressed under tissue-specific promoter

superposition lox ->gene between not transcribed

floxed target gene

cells with active Cre recombinase: original gene function is disrupted, the reporter gene is transcribed instead

cells lacking active cre recombinase: original gene function is untouched

Cre linked to molecule recognizing tamoxifen -> when injected KO

induce KO at adult age

normal development, otherwise compensatory mechanisms possible

allows mutations, deletions or insertion (KI)

overexpression possible

catheters to increase insulin level ->decrease glycemia

if glucose-sensitive ->need more glucose, glucose infusion rate = proportional to insulin sensitivity

use radio-isotope ->can be detected if hydrolyzed water -> more 3H2O

look at quantity in muscle ->how much was taken up