Terapie - inzulíny

Terapie inzulínem DM1

• The treatment combines INGAP Peptide (Exsulin), which stimulates growth of the insulin secreting islets, and ustekinumab (Stelera), a drug approved for the treatment of psoriasis. This is the first study that combines a specific islet regeneration agent and a treatment to control autoimmune attack of the newly formed islets. INGAP Peptide is the result of pioneering research by Dr. Lawrence Rosenberg, Professor of Surgery and Medicine, McGill University and President and CEO of the Integrated Health & Social Services University Network for West-Central Montreal, and his collaborator Dr. Aaron I. Vinik, Director of Research and Murray Waitzer Endowed Chair for Diabetes Research at the Eastern Virginia Medical School (EVMS). Dr. Vinik and his colleagues identified the specific INGAP Peptide after Dr. Rosenberg demonstrated islet regeneration can be induced and isolated the islet regeneration activity. The study is jointly led by Dr. Rosenberg and Dr. George Tsoukas, Senior Endocrinologist and Associate Professor of Medicine, McGill University Health Centre.

The design of the study is based on previous trials of INGAP Peptide alone, which demonstrated improvement in insulin secretion and glucose control in both type 1 and type 2 diabetes patients. The addition of ustekinumab, an interleukin-12 inhibitor, is based on research by Dr. Jerry Nadler, Chair of Medicine and Vice Dean of Research at EVMS, which showed the islet restoring effect of INGAP peptide was enhanced by the addition of another IL-12 inhibitor. [30]

• A few therapies have been tested in humans for islet regeneration activity, but only INGAP Peptide has been specifically developed and tested in patients for this purpose. It is clear that both kinds of treatment will be required to cure type 1 diabetes." [30]

• A phase II clinical trial testing the ability of the generic vaccine bacillus Calmette-Guérin (BCG) to reverse advanced type 1 diabetes has received approval from the U.S. Food and Drug Administration (FDA). [37]
• The five-year trial will investigate whether repeat BCG vaccination can clinically improve type 1 diabetes in adults between 18 and 60 years of age who have small but still detectable levels of insulin secretion from the pancreas. Faustman's research team was the first group to document reversal of advanced type 1 diabetes in mice and subsequently completed a successful phase I human clinical trial of BCG vaccination. She announced the FDA approval to launch the phase II trial during her ADA presentation [37]
• BCG is currently approved by the FDA for vaccination against tuberculosis and for the treatment of bladder cancer. The vaccine is known to elevate levels of the immune modulator tumor necrosis factor (TNF), which Faustman's team previously showed can temporarily eliminate in both humans and mice the abnormal white blood cells responsible for autoimmune type 1 diabetes. Increased TNF levels also stimulated production of protective regulatory T cells. [37]
• In the phase I clinical trial, which was published in the August 8, 2012, issue of PLOS Medicine, two injections of BCG spaced four weeks apart led to temporary elimination of diabetes-causing T cells and provided evidence of a small, transient return of insulin secretion. The phase II clinical study will include more frequent dosing over a longer time period to determine the potential of repeat BCG vaccination to ameliorate the autoimmune state and improve clinical parameters such as HbA1c, a marker of average blood sugar control.

In the new trial, which will be double blinded and conducted at MGH, 150 adults with long-term type 1 diabetes will be randomized to receive two injections four weeks apart of either BCG or placebo and then a single injection annually for the next four years. Patients will be closely monitored over the five-year trial period. The primary outcome measure will be improved results on the HbA1c blood test, which have been shown to prevent complications.[37]

• Generated functional human ß cells from hPSCs in vitro without any genetic alterations of the cells. The ß cells, which were generated following sequential differentiation resulting from high-glucose challenges, were structurally and functionally similar to pancreatic ß cells. Mice transplanted with these cells could secrete insulin and reduce hyperglycemia.3 - [68]

• Clinical immune interventions have been conducted, but immune-modulators such as rituximab and otelixizumab showed functional variability based on age and ethnicity. [68]

• Vaccination with HLA-binding peptide epitopes is another option, though several challenges remain, including a person’s HLA haplotype, defining the route of administration, and the dose and frequency of administration. Trials examining the efficacy of cell therapy with FOXP3+ TREG cells to halt T1DM progression are presenting encouraging results in preliminary studies. However, the specificity of the FOXP3+ TREG cells to selectively suppress islet autoimmunity, as well as stability of their cells, remains questionable.4 - See more at: http://www.ajmc.com/journals/evidence-based-diabetes-management/2015/january-2015/preventing-beta-cell-destruction-in-t1dm#sthash.f3vdU0FF.dpuf [68]

• In their attempt to find a cure for T1DM and to help rid patients of their daily insulin dose, investigators at the University of Alabama at Birmingham (UAB) have designed a clinical trial to evaluate the blood pressure medication verapamil for use in T1DM.5 To be initiated early this year, the trial, funded by a multi-million dollar grant from the Juvenile Diabetes Research Foundation, is based on preliminary evidence from a mouse model, which showed that the commonly used blood pressure medication could completely reverse diabetes in mice.6

Research conducted in the laboratory of Anath Shalev, MD, director of UAB’s Comprehensive Diabetes Center, found that administering oral verapamil could prevent ß-cell death in mice with T1DM. How? The authors found that verapamil repressed the expression of thioredoxin-interacting protein (TXNIP), a gene whose glucose-regulated expression is induced in the islets of diabetic individuals, resulting in ß-cell death.6 TXNIP also induces the expression of IL-1ß, a cytokine that promotes T1DM. Following their discovery that verapamil can inhibit the expression of TXNIP,7 Shalev’s research team evaluated the drug in vitro in pancreatic ß cells, and in vivo in mice, and found that verapamil-mediated downregulation of TXNIP prevented ß-cell apoptosis, improved ß-cell survival and function, and rescued mice from diabetes. Importantly, verapamil could regulate TXNIP expression only in the presence of elevated glucose levels, which offsets any unwanted side effects due to excessive reduction of TXNIP below physiological levels.6

• See more at: http://www.ajmc.com/journals/evidence-based-diabetes-management/2015/january-2015/preventing-beta-cell-destruction-in-t1dm#sthash.f3vdU0FF.dpuf [68]

THE VERAPAMIL TRIAL

The trial aims to enroll 52 people, 19 to 45 years of age, within 3 months of being diagnosed with T1DM. These patients will be initiated on a placebo or verapamil while on their insulin pump therapy, and blood glucose will be monitored using a continuous glucose monitoring system.5 In an e-mail, Shalev informed Evidence-Based Diabetes Management that the trial, which has already been initiated will continue to enroll adults within 3 months of being newly diagnosed with T1DM, until spring 2016.

The current trial will follow patients for a period of 1 year after initiating verapamil. However, Shalev informed EBDM that funding permitted, encouraging results from the current trial would be followed-up with a longer-term trial to observe more sustained effects of verapamil. “We definitely would like to conduct a longer-term trial, as 1-year may indeed be rather short to see the full extent of the effects in humans. At that point, we would also like to expand our inclusion criteria to allow patients with slightly longer disease duration to participate,” wrote Shalev.

Although it’s early to predict verapamil adoption in practice, Shalev hopes it will be, considering that the molecule has already been used in clinic for other indications for 30 years. “So, adaptation into clinical practice would only require official repurposing. At least until more specific strategies are being developed and tested down the road, it would provide a unique approach trying to enhance the patient’s own beta cell mass and insulin production,” Shalev anticipates. Additional information on the project can be found at http://www.uab.edu/medicine/diabetes/new-clinical-trial.

• See more at: http://www.ajmc.com/journals/evidence-based-diabetes-management/2015/january-2015/preventing-beta-cell-destruction-in-t1dm#sthash.f3vdU0FF.dpuf [68]

• Embryonic stem cells and induced pluripotent stem cells achieve high levels of ß-cell differentiation, but their clinical use is still hampered by ethical issues and/or the risk of developing tumors after transplantation. Pancreatic epithelial cells (duct, acinar, or ?-cells) represent an appealing alternative to stem cells because they demonstrate ß-cell differentiation capacities.

• Transdifferentiation, also known as lineage reprogramming,[1] is a process where one mature somatic cell transforms into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type.[2] It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine.[3] The term 'transdifferentiation' was originally coined by Selman and Kafatos[citation needed] in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis.[4]
• Ferber et al.[8] by induce a shift in the developmental fate of cells in liver and convert them into 'pancreatic beta-cell-like' cells. The cells induced a wide, functional and long-lasting transdifferentiation process that reduced the effects of hyperglycemia in diabetic mice.[9] Moreover, the trans-differentiated beta-like cells were found to be resistant to the autoimmune attack that characterizes type 1 diabetes [10]

The second step was to undergo transdifferentiation in human specimens. By transducing liver cells with a single gene, Sapir et al. were able to induce human liver cells to transdifferentiate into human beta cells.[11]
This approach has been demonstrated in mice, rat, xenopus and human tissues (Al-Hasani et al., 2013).[citation needed]
Schematic model of the hepatocyte-to-beta cell transdifferentiation process. Hepatocytes are obtained by liver biopsy from diabetic patient, cultured and expanded ex vivo, transduced with a PDX1 virus, transdifferentiated into functional insulin-producing beta cells, and transplanted back into the patient.[95]

• Rearrangement of the chromatin structure via DNA methylation or histone modification may play a role as well.[16] Here is a list of in vitro examples and in vivo examples. In vivo methods of transfecting specific mouse cells utilize the same kinds of vectors as in vitro experiments, except that the vector is injected into a specific organ. Zhou et al. (2008) injected Ngn3, Pdx1 and Mafa into the dorsal splenic lobe (pancreas) of mice to reprogram pancreatic exocrine cells into ß-cells in order to ameliorate hyperglycaemia [95]

(fibroblasts, keratinocytes, and muscle cells) and developmentally related cells (hepatocytes, gastrointestinal, and pancreatic exocrine cells) have been successfully reprogrammed into ß cells in vitro and in vivo. However, while some reprogrammed ß cells bear similarities to bona fide ß cells, others do not develop into fully functional ß cells. Here we review various strategies currently used for ß cell reprogramming, including ectopic expression of specific transcription factors associated with islet development, repression of maintenance factors of host cells, regulation of epigenetic modifications, and microenvironmental changes. Development of simple and efficient reprogramming methods is a key priority for developing fully functional ß cells suitable for cell replacement therapy.

• Proof that a normal number of functioning beta-cells can be restored in a pancreas in which essentially all of the beta-cells had been destroyed, a situation analogous to type 1 diabetes. compound (BI6015), and tested it in normal mice as well as diabetic mice in which the beta-cells had been destroyed. In both types of mice, BI6015 stimulated a large amount of beta-cell replication. This study is important because it provides a pharmacologically relevant means to stimulate the formation of a large number of new beta-cells, which is necessary for the development of a new treatment for diabetes. [97]
• The compounds under investigation increased beta cell mass by coaxing NFATc1 into the nucleus. [99]

The one definite environmental factor is congenital rubella, because of which a subset of children subsequently develop type 1 diabetes. The putative predisposing factors are viruses, gluten and cow's milk. The putative protective factors include gut flora, helminths, viral infections, and Vitamin D. Prevention of T1DM can include: Primary prevention strategies before the development of autoantibodies and Secondary prevention regimens after autoantibody development. Once islet cell autoantibodies have developed, the goal is to establish a therapeutic regimen to preserve at least 90% of the beta cells, and prevent the development of hyperglycaemia. The targets for T1DM reversal should include autoimmunity, beta cell regeneration and protection of beta cell mass. Anti-CD3 teplizumab and anti-CD3 otelixizumab have been shown to provide C-peptide preservation. The unanswered questions in diabetes research include elimination of autoimmune memory responses, reestablishment of immune self-tolerance, and mechanisms of disease initiation. [99]

• Bone marrow cells give rise to insulin-producing cells in the pancreas13 (and even in other organs in a hyperglycaemic animal14) although this idea has been contested15 and one other study shows that bone marrow cells favour replication of existing beta cells16. Most recently, the field has been challenged by an elegant genetic lineage study claiming that in adult mice, even following partial pancreatectomy to trigger regeneration, replication of existing beta cells is the overwhelmingly dominant pathway for the formation of new beta cells17. The authors conclude that their study closes the door on the existence

Studies demonstrating insulin production in the liver have caught the attention of the community. Clearly, the ability to drive extra-pancreatic cells to express insulin and ultimately to assume a true beta-cell phenotype could be useful not only in the context of generating large numbers of cells for implantation but also for (ectopic) regeneration of beta cells in vivo. Insulin expression was observed in a limited number of cells with reversal of diabetes after in vivo infection of the liver of hyperglycaemic mice with recombinant adenovirus expressing the pancreatic and duodenal homeobox gene 1 (PDX-1, also known as IPF-1)23 or by expression of this same factor along with telomerase in fetal human progenitor liver cells in vitro followed by implantation in hyperglycaemic mice24. The latter study seems particularly encouraging for possible future cell-based therapy of diabetes in that human cells with impressive replicative capacity were used. The first study is also captivating in that it suggests adult liver may also provide a source of beta cells.

• Immunotherapy intervention trials in new onset type 1 diabetes mellitus

MMF and DZB – Peter Gottlieb, TrialNet

HSP 65 p227 s.c. (Peptor) – Jerry, Palmer, Seattle

Multi-dose DZB – Henry Rodriguez, Indiana

Exenatide and DZB – David Harlan, NIH

Oral hIFN – alpha – Kristina Rother, NIH

Anti-CD20 – Mark Peskovitz, Indiana, TrialNet

Anti-CD3 – Protégé Macrogenics

Multidose anti-CD3 hOKT – Kevan Herold, ITN

Rapamycin and IL-2, Greenbaum – ITN

CTLA4Ig – Tihamer Orban, TrialNet

Glutamic acid decarboxylase 65 in Alum – Diamyd

Pro-insulin DNA Vaccine – Bay Hill

ATG (Sandostat) – Steve Gitelman, UCSF, ITN, TrialNet

Gastrin and EGF– Phase I Trial

Alpha 1 anti-trypsin trials: Peter Gottlieb – BDC and ITN.

Cyclosporine immunotherapy was associated with an increased remission rate in recently diagnosed T1DM (approach abandoned because of associated nephrotoxicity). Anti-CD3 teplizumab and anti-CD3 otelixizumab have been shown to provide C-peptide preservation. Potential of combination therapies are being explored (combination of immunotherapy, beta cell protection/regeneration therapies etc). :99::

Terapie inzulínem DM2

• Combination of basal insulin with a GLP-1 agonist resulted in a 92% greater likelihood of achieving target blood sugar control (A1c of 7% or lower), with similar rates of hypoglycaemia and an average weight loss of more than 3kg compared with other anti-diabetic treatments. Compared to full basal-bolus insulin regimens, the combined treatment generated modestly better blood sugar control, but had a 33% lower risk of hypoglycaemia and almost 6kg greater weight loss. [24]
• The major barrier to widespread adoption of these treatments is cost—both GLP-1 agonists and insulin analogues are among the most expensive in diabetes care. The major barrier to widespread adoption of these treatments is cost—both GLP-1 agonists and insulin analogues are among the most expensive in diabetes care. [24]

-SGLT-2 inhibitors are the newest class of drugs that inhibits the reabsorption of glucose in the kidney. By inhibiting the reabsorption of glucose, SGLT-2 lowers blood glucose levels and prevents hyperglycemia.

Základní typy, charakteristiky inzulínů a jejich použití

• Schémata vč. parametrů titrací a výpočtu bolusu v tabulce viz zde

Obecné charakteristiky inzulínů

Aktivita inzulínu

• "v jednotkách" - IU
• Standardní preparáty
• Cca 25 jednotek / 1 mg krystalického inzulínu [9,6]
• V ČR užívané inzulinové lahvičky a cartridge
• 100 IU inzulinu v 1 ml
• Humalog 200 IU/ml
• Glargin 300 IU/ml pod názvem Toujeo [6]

Aplikační formy

• Naředěné roztoky k s.c., i.m., ev. i.v.

Zvířecí inzulíny

• Z vepřových nebo hovězích pankreatů
• Především z jatečních vepřů a skotu
• Prakticky nahrazen inzulinem humánním

Vepřový inzulin

• Liší se pouze v jedné aminokyselině

Hovězí inzulín

• Liší se ve 3 AMK
• Jen minimální vliv na účinnost / tolerování [6]

Humánní inzulíny

3 Dělení dle způsobu získávání

Syntetický inzulin

• Vysoce čištěný, neutrální vodný roztok
• Vázaný se zinkem
• Látky ovlivňující délku účinku inzulinu
• Konzervační látky
• Stabilizující látky

Dělení dle rychlosti a délky účinků inzulínů

Humánní inzulíny

Rychlé humánní inzulíny

• Vstřebávání pomalejší než rychlá analoga
• účinek až po 30 min.
• Aplikace 30 - 45 min. před jídlem
• Delší účinek než analoga
• Bolus na hlavní jídlo pokryje i svačinu, která je často nutná
• Vyšší riziko hypoglykémií
• Obtížnější redukce hmotnosti
• Ne do pumpy
• Vadi silikon i heparin, alkohol, desinfekce
• Zkřížené alerg. reakce na zvířecí inzulíny
• čiré, neutrální roztoky bez přípravků zpomalujících absorpci [8]
• žluté [6]
• K i.v. (jako jediné!) aplikaci [8]
• Lze s.c. i i.m. [8]
• Vrchol účinku - za 1–3 h
• Konec účinku - za 4–6 h
• úměrné velikosti dávky [8]

Insulin HM-R

Actrapid HM

Humulin R

Insuman Rapid

Velosulin

• Pufrovaný přípravek určený k použití v inzulínových pumpách [8]

Středně dlouho působící humánní inzulíny

NPH (Neutral Protamin Hagedorn)

• Depotní inzulín
• 2xd
• V ampuli mléčně zabarvený - suspenze
• Před upotřebením protřepat
• Změnou fyzikálně chemických vlastností přípravku
• Snížením jeho rozpustnosti
• Zpomalením absorpce inzulínu z podkoží
• Začínají působit za 1–2,5 h
• účinek vrcholí za 4–12 h
• účinek končí za 12–16 h [8]

HM-NPH

• NPH insulíny zelené [6]

Insulatard HM

Humulin N

Insuman Basal

Dlouhodobě působícím humánní inzulíny - Velmi dlouho působící inzulíny

• Lidský inzulín
• Polypeptid obsahující 51 aminokyselin
• Semisynteticky z vepřového inzulínu záměnou odlišné aminokyseliny
• Biosynteticky pomocí přenosu genové informace do buňky E. coli či Saccharomyces cerevisiae
• Začínají působit za 2–3 h
• účinek vrcholí za 10–18 h
• účinek odeznívá za 24–36 h [8]

Ultratard HM

Stabilizované směsi inzulínu

• Krátce účinkující inzulín a NPH inzulín v různých poměrech
• Nejčastěji
• 20 : 80
• 30 : 70
• 40 : 60
• 50 : 50

Mixtard 20, 30, 40, 50,

Humulin M3

Insulin HM-mix 30

Inzulínová analoga

Krátkodobě působící analoga

• Lepší kompenzace postprandiální hyperglykemie než humánní rychlé inzulíny
• Nižší hodnoty glyk. Hb
• Rychlá absorpce, účinek od 10-15 min.
• Aplikace těsně před jídlem nebo i až 15 min. po
• Nástup hypoglykemie může být rychlejší
• Kratší celkové působení
• Menší riziko hypoglykémií
• Vyšší volnost v jídelníčku včetně možnosti dodržet delší pauzy mezi jídly
• Pokud je pauza delší než 5h, nedochází k výrazné sumaci účinků inzulínu z předchozí dávky.
• Dávají se i do inzulínových pump.
• Vrchol účinku za 30 min. [8]
• Odeznívání účinku do 3–4 h [8]

Aspart (NovoRapid):

• Substituce AMK prolinu kyselinou asparagovou na pozici B28
• Snižuje tendenci ke tvorbě hexamerů, která je pozorována u rozpustného humánního inzulinu
• = rychleji se vstřebává z podkoží ve srovnání s rozpustným humánním inzulinem

Glulisin (Apidra)

• Náhrada AMK asparagin na pozici B3 lidského inzulínu lysinem a lysinu na pozici B29 kyselinou glutamovou
• Snížení dimerizace inzulinové molekuly [12]
• Změna v pozici 3 představuje prevenci tvorby hexamerů v přítomnosti zinku - urychlení absorpce [12]
• Poklesu izoelektrického bodu
• 5,5 pro humánní inzulin, 5,1 pro glulisin [12]
• Zlepšení rozpustnosti inzulinu při fyziologickém pH
• Konzervační látka
• Není užit fenol
• Je pufrován trometamolem [12]
• Stabilizátor
• Polysorbát [12]
• Hygroskopický prášek
• Roztok je průhledný, čirý [12]
• Jedna jednotka inzulinu glulisinu odpovídá 34,9 mg [12]
• Celková doba absorpce a působení do 4,5 hodiny i ve velkých D [13]
• Absolutní biologická dostupnost cca 70%
• Srovnatelná hodnota s ostatními inzuliny
• Nezávislá na místě aplikace [13]
• Farmakokinetika ani farmakodynamika inzulinu glulisinu nekorelovala s:
• Indexem tělesné hmotnosti
• S tloušťkou podkožního tuku. [13]
• Proti lidskému inzulínu zlepšuje kompenzaci
• Zejména postprandiální glykémii
• Nezvyšuje riziko hypoglykémie
• Zvyšuje flexibilitu režimu
• Možnost aplikace těsně před jídlem [13]
• Rychlejší účinek u obézních proti inzulinu lispro
• Lepší stabilizace molekuly polysorbátem 20 namísto zinku
• Vliv na apoptózu ß-buněk v buněčných kulturách [13]

Lispro (Humalog)

• Záměnou pořadí AMK v pozici B28 a B29 [8]
• V ploše pod křivkou inzulinémie v časné fázi měl inzulin lispro lehce zpožděný nástup aktivity proti glulisinu [13]

Směsi s krátkodobými analogy

BiAsp 30 (Novomix 30)

• 30% krátkého inzulínového analogu aspart a 70% retardované formy téhož
• V konvenčních i intenzifikovaných inzulínových režimech
• S aplikací analogu aspart v poledních hodinách [8]

Dlouhodobě působící inzulínová analoga - Pomalá inzulínová analoga

• Nemají peak
• Působení (až 24 hodin), stačí i 1xd
• Menší riziko nočních hypo
• Mohou být čirá [6]

Glargin (Lantus, Absalgar, Toujeo, Optisulin)

• Adicí 2 argininů k C-konci B řetězce a náhradou asparaginu glycinem na pozici A21
• Málo rozpusntý při neutrálním pH
• úplně rozpustný při pH 4 (v lahvičkách k aplikaci)
• V podkožní je neutralizován
• = vznik mikroprecipitátů - hexamerů
• = pomalé plynulé uvolňování - nemá peak
• Účinek dán především expozicí metabolitu M1.
• Také vazba na inz. rec., 5-8 x silněji k IGF-1 rec. než inzulín, 70-80 slaběji než IGF-1
• Aktivace mitogenní cesty via IGF-1 rec. neblya při terapii pac. s DM1 dosažena (SPC SÚKL)
• Studie (Hemkens et al.) zjistila vztah mezi užíváním inzulinu glargin a malignitami v závislosti na dávce.
• Nejsou však dostupné informace o typech karcinomů nalezených v této studii.
• Na základě v současné době dostupných údajů nemůže být vztah mezi inzulinem glargin a karcinomem potvrzen ani vyloučen. (SUKL)

Detemir

• Adicí kyseliny myristové do pozice B29 a odstraněním aminokyseliny v pozici B30
• Pomalé uvolňování za pomoci kyseliny myristové [6]

Degludec (Tresiba)

Levemir

Novinky v léčbě a výzkum

Inhalační inzulin (Exubera)

• Množství inhalovaného inzulinu větší než při s.c.

Porty vpravující inzulín do peritoneálního prostoru

• Připojené k zevně umístěné inzulínové pumpě

Implantabilní inzulínové pumpy

• Umístěné přímo v peritoneálním prostoru

Inzuíny	Výroba	Nástup účinku	Peak účinku	Doba účinku	dávek/d	Obvyklá dávka	Titrace	Specifika
Lispro (Humalog, Lisprolog)	E. coli	Do 10-15 min.	30-70 min	2-5h	3 +		lze apl. i 15 min. po jídle	Lze s.c., pumpou, i.m., i.v., se sulfonylureou
Aspart (Novorapid)	Saccharomyces cerevisiae	10-20 min.	1-3h	3-5 h (norm. 4-6h)	3 +
Glulisin (Apidra)		10-20 min.		Prům. 98 min., (T1/2= 42 min), až 6-8h (?)	3 +
Actrapid	Saccharomyces cerevisiae	30 min.	1,5–3,5h	7–8h (T1/2=2–5h)	3 +	0,5 - 1,0 IU/kg tělesné hmot./d
Humulin R	E. coli	20-30 min.	2-4-6h	10-12h	3 +
Insulin Human Winthrop Rapid	E.coli	30 min	1-4h	7-9h	3 +		apl. 15-20 min před jídlem
Insuman Rapid	E. coli	30 min	1-4h	7-9h	3 +	0,5-1,0 IU/kg/d
Glargin (Abasaglar, Lantus)	E. coli						ustálení hl. za 2-4 dny po 1.D	méně nočních hypo., více ranních hypo (sumace)
Glargin (Toujeo)	E. coli			až 36h	1xd ráno / večer	0,42 IU/kg/d	počáteční D 0,2 IU/kg a titrovat
NPH			až 36h	1xd ráno / večer	0,42 IU/kg/d	počáteční D 0,2 IU/kg a titrovat

Cvičné otázky pro nelékaře:

Má inzulín vliv na plod v děloze ?

Má podaný inzulín vliv na kojence? Proč?