MEDICAL OVERUSE:WHO SHOULD CONTROL AND STOP IT?

Almost at the same time the Bertelsmann Foundation(05.11.2019) and JAMA(Journal of American Medical Association)Internal Medicine (published online september 9,2019) published data on overuse of the medical system including laboratory testing, radiological testing, medical (over)treatment ( antibiotics in urgent care clinics) and surgical (e.g. thyreoidectomy)interventions.
Both publications came m0re or less to the same conclusions „the findings suggest that many tests are overused,overtreatment is common,and unnecessary care can lead to patient harm“.
Therefore politicians should start a broad information campaign for all workers and employers who pay for health insurance and who sustain the health system.After that they should start to control the system more closely and to reduce expences. May be privatisation of the health care system and adoption of the „american“ DRG-system was not as successful as it was suggested it would be when both were introduced into the european systems more than 15 years ago.In fact now both sides of the atlantic independently from eachother come to the same conclusions:at least one third of the expenses can be avoided and even a better quality of the health care system with less patient harm could be the consequence.

Grote-Westrick,Marion,Münch Inga,Volbracht Eckhardt.Überversorgung schadet den Patienten.BertelsamnnStiftung05.11.2019
Morgan DJ,Dhruva SS, Coon ER,Wright SM, Korenstein D.:2019Update on medical overuse.A Review.JAMAInternal Medicinepublished onlin september 9;E1-7

ACADEMIC MEDICAL CENTERS (AMCs):How much is still academic?

This is a summary accompanied by some personal comments of a very recent Viewpoint report(Academic medical centers.Too large for their Own Health?) published in JAMA (june 17,2019,E1,E2) by S.Claiborne Johnstone (Dell academic medical school,university of texas,Austin)

1) fully accreditated medical schools(141) in the US not only educate medical students but they mainly „operate clinics and own hospitals“ defined as „Academic Medical Centers“ (AMCs)

It would be interesting to know how the accreditation procedure works.Who decides about the qualification of the teaching personnel and about the scientific quality of the publications? Deans of medical faculties are judged on the basis of the „quality“ of researchers they are able to hire The researchers are judged on the basis of their publications and of their funding.However there is no way to check the quality of the scientific production independent of the scientific journal lobby. More and more researchers within AMCs have not studied medicine.They can not even judge the real impact of their research on medical pathology.

2)56% of the AMCs have annual revenues greater than 500 million dollars.

The crucial question raised by the author is : „have some AMCs grown to large to survive a changing health care system,much less to lead the change required?“

In other words can the AMCs lead the necessary structural(dimension ) reduction by reducing the number of treatments to those really needed?

Or do the economical and occupational constraints dominate the scientific knowledge which seems to suggest that less is more for the comunity?

3)„AMCs generate an estimated 6.3 million jobs and contribute an estimated 562 billion dollars to gross domestic product“

  That is to say that each employee contributes with his medical insurance fee to the maintenance of the largest employers in many cities hosting AMCs.

4)„At the same time, academic medicine has contributed to the creation of a suboptimal health system.“

5)„The World Health Organisation ranks the US health care system 37th among countries worldwide,just above Cuba“

6)„and life expectancy has declined in the United States during the last 3 years“.

7)„health care costs in the united states are 25% greater than the second most expensive country and 14-fold greater than Cuba`s“.

That is to say that  „scientific progress“ contributes to increased expenses for the health care system but not to prolong life expectancy in a country with the most expensive health care system which, however, ranks  just above that of Cuba, still a comunist country. On the contrary,decreasing life expectansy  may be also because of an „aggressive“ DRG-based  health care system mainly working for profit  „.

8) „AMCs are major sources of health care in nearly every US metropolitan area,and costs of care at virtually all AMCs are particularly high“

9)„so there is no denying that they have contributed to the health care system that currentlx exsists“

This is a polite way to express the concept that AMCs,which are supposed to path the way for the rest of the health system by mainly contributing to the medical guidelines, instead of becoming more and more restrictive, are developing toward a growing business branch.This of course influences the consideration given (mostly by the CEOs) to less aggressive and chipper diagnostic and therapeutic procedure in comparison to more aggressive and more expensive tools with a disavantage for the patient. In fact,if the system can not be made responsible for the reduction of life expecatncy,it does not seem to be able to stop this trend.

10)„the shiftng balance of the three major missions of AMCs-education,research, and clinical care-underlies the current challenge“

This is a crucial point. Education and research , existing within the same structure,can not be other than dominated by the economical constraints of clinical care,which forces to rewrite physiology , pathology,diagnostic and therapy toward profit oriented SOPs(standard oerating procedures) combined with ultra short permanence in the clinic.

Internal medicine has become much less important than surgery.

11)„however, the proportion of medical school funding derived from research has declined more recently,with federal grants making an average of 14% of medical schools revenues (Figure),with industry and foundation funding accounting for another 9%.“

12)“ from this perspective,funded research is actually a modest function of medical schools and their associated AMCs.Clinical revenue dearly is the dominating source of revenue at virtually every AMC.“

What we really would like to know is how many AMCs are in private hands,and how much private funding influences non private funding by lobbying work into the review system.How much is the educational system including scientififc society meetings,therapeutic tryials and scientific journals influenced by private interest groups? The continous advertising within the health care system does not make it different,if not even worse than other commercial branches with little possibility of defence for the „consumer“,in this special case, the sick patient.

13)„As greater and greater margins were realized from these faculty clinicians with revenue exceeding costs,more were hired and clinics and hospitals were constructed to support them“

14)“ These trends have accelerated during the last 20 years,with many faculty devoted nearly to clinical care“

At the same time the scientific world is asking itself why is the figure of the  physician scientist  within the AMCs disappearing ?

15)„Thus many of today`s AMCs are similar to huge tankers loaded with health care services,and research and education are merely passengers“.

The consequence of this developement is much worse.As mentioned above, the chief of administration are the true deus ex machina.They decide about who is going to be hired und who is „disturbing“ the business within the clinical teams. Honest medicine is in the middle of two enemies, the industry and the administrators of the clinical every day life.

15)„there is the  crux of the issue :any changes threatening the margins from clinical care will affect the intire mission of an AMC“.

This consideration does not take into account that  part of the revenues of the clnical care goes into the pocket of private investors at total disavantage of the fee-payers. This money influences the fate of  „honest“ medicine.

16)„Academic medical centers tend to do well in negotiating reimbursement rates from insurers,and they tend to admit patients who require more expensive and invasive interventions.“

This assumption goes back to the time where medical knowledge about tissue damage leading to organ dysfunction was poor and patients with acute or  with terminal organ insufficiency  made the bulk of the patient population. Conservative medicine has however made giant progresses and many invasive procedures (even oragan transplantation) are much less necessary than it was 20-30 years ago when patient presented with more advanced disease stages.

17) „Thus by necessity,the majority of AMCs are inclined to stay the course of the current health care system.“

18) “ A move to value-based care is more than just risky;it is counter to their best interests unless a clear line of sight to new payment models exists.

In fact so far using the DRG-system no attention  was paid to quality of medical treatment as it is not considered by the reimbursement system. For this reason number and quality of the persons involved in treatment was less important than costs.

 

19)„In the fee-for-service payment system, preventig illness and reducing wasteful diagnostics  or unnecessary treatment could reduce the income of AMCs (as well as other medical centers)“.

20)„Although many reports that have described the need to reallocate resources toward prevention,population health, and value-based care come from medical school faculty, the leaders of the AMC clinical enterprise will tend to resist change because it puts the entire institution at risk“.

21)„Faculty can discuss population health and value,but may be stymied from making important progress“.

22)„In this way,academic medicine is not fully aligned wih society´s interest in optimizing health outcomes or in reducing waste.“

23)„To better align with society´s interests,AMCs must reduce their reliance on fee-for -service medicine and the associated pressures to retain market share,raise prices,and increase consumption of health care.“

24)„Instead,they should leverage their expert leaders to develop and coordinate new models of care,focusing on solutions that enhance value„.

25)„If payers are reinbursing for value,the planning and coordination role naturally payed by AMCs could produce revenues that exceed costs.“

26)„Academic medicine could then lead in innovation and coordination of new models of care,being paid for value without necessarily owing all components of the system“.

27)„Academic medical centers should be optimized to enable rapid innovation in health that aligns with society´s interests.“

28)„Getting this alignement right will not be easy,particularly in an industry that has rewarded the traditional fee-for-service model with fairly reliable margins“

29)„Similar to a nimble schooner,an AMC that can alter course quickly and test new waters may be more valuable to society than megatanker,particularly given the narrow straits ahead“.

This would however mean reduction of the number of beds and of the number of employees,which is politically very inconvenient.

 

Republik Kongo (DRC) bedroht die Ausrottungsanstrengungen. Polio-Ausbruch in der Demokratischen Das Virus aus dem Polio-Impfstoff breitet sich aus trotz der Notmaßnahmen.

Während des Ebolaausbruchs in der DRC ist der Polio-Ausbruch in den Hintergrund geraten. Trotz der seit Monaten andauernden Anstrengungen breitet sich die Infektion aus. Mittlerweile sind 29 Kinder an der Lähmung erkrankt. Starke Besorgnisse hat der Fall ausgelößt, der am 21 Juni an der Grenze zu Uganda gemeldet wurde. In der Tat hat sich der Fall weit von der ursprünglichen Ausbruchsgegend entfernt ereignet.

Dieser Ausbruch wurde nicht vom Virus-Wildtyp bestimmt, wie es noch in Afganistan, Pakistan und vielleicht Nigeria der Fall ist, sondern von einer seltenen Mutante des Serotyps 2 aus der früheren oralen trivalenten Polio-Vakzine (OPV)

In der Tat, während die OPV-Impfkampagnen fast zu totaler Ausrottung des Wildtyps geführt haben, ist die Zirkulation des aus der Vakzine-entstandenen Viruses (cVDPVs) eine erneute Gefahr für die Länder geworden,die bislang frei von Polio waren und kann das ganze Projekt gefährden. Mittlerweile ist die Beseitigung dieses Ausbruches durch den Serotyp 2 fast wichtiger geworden als die Ausrottung des Wildtyps  . In armen Ländern, wie DRC kann es passieren, dass attenuierte Viren aus der alten trivalenten Vakzine an die vielen Kinder weitergegeben werden, die nicht geimpft worden waren. Dadurch konnte das Virus jahrelang im Umlauf bleiben. In dieser Zeit konnte das Virus derart mutieren, dass es gefährlich werden konnte. Die große Mehrzahl dieser Viren (cVDPVs) gehört zum Serotyp 2 der ursprünglich (bis 2016) zu den drei Varianten des OPV- Impfstoffes (1,2,3) gehörten. Diese Variante wurde dann entfernt, weil der Serotyp 2 in der Weltbevölkerung als ausgerottet galt aber als Ursache für die seltenen Lähmungen als Impfkomplikation (1:1 Million) nach Impfung mit dem trivalenten Impfstoff bei geimpften Kindern festgestellt wurde. Im April 2016 wurde die trivalente Vakzine in 155 Ländern der Welt durch die bivalente (ohne Serotyp 2) ersetzt. Obwohl niemand richtig wusste, wie es ausgehen würde, hatte man weiterhin mit seltenen Fällen von Lähmungen durch Serotyp 2 gerechnet. Zur Verhinderung der Entstehung von größeren Ausbrüchen wurde eine Serotyp 2 -„Einzelvakzine“  (monovalente),mOPV2,hergestellt.Die Entscheidung , diese Vakzine einzusetzen wird von dem WHO-Generaldirektor getroffen.

Seit 2016 ist diese Vakzine in 10 Ländern angeordnet worden.

Obwohl diese Strategie zu funktionieren scheint, hat Serotyp 2 im letzten Jahr in Syrien 74 Fälle von Kinderlähmungen verursacht, bevor der Ausbruch für beendet erklärt werden konnte.

Der Ausbruch in DRC wurde im Juni 2017 in der Provinz Maniema in der Mitte des Landes erstmals entdeckt. Nach wenigen Tagen wurde der zweite Fall 900 Km entfernt im Südosten des Landes (Provinz Haut-Lomani) erfasst. Eine genetische Analyse beider Viren zeigte, dass es sich um zwei unterschiedliche Stämme des cVDPV2 handelte und dass die

Viren in den letzten 2 Jahren unbemerkt zirkuliert hatten. Es wurde mit der mOPV2-Vakzinierung in 8 Distrikten begonnen,

die als am meisten gefährdet angesehen wurden. Da man nicht alle entfernten Dörfer erreichen konnte, konnte sich das Haut-Lomami-virus  nach Süden nach Tanganyka und dann auch nach Haut-Katanga ausbreiten. Anfang Juni 2018 wurde ein weiterer Fall auf der anderen Seite des Landes bestätigt. Dort war auch Ebola ausgebrochen. Auch in diesem Fall handelte es sich um einen von den anderen unabhängigen Stamm als Hinweis für die schwache Überwachung in DRC. Noch alarmierender ist der Fall, der zwei Wochen später im Nordosten des Lander in der Nähe der Grenze zu Uganda gemeldet wurde. Das Haut-Lomani-Virus hatte einen Sprung in den Norden getan, in eine Gegend, wo keine mOPV2-Impfung zur Eindämmung der Ausbreitung diesen Stammes stattgefunden hatte. Sollte es zu einer größeren Ausbreitung innerhalb Afrikas kommen, müsste die trivalente Vakzine wieder eingeführt werden. Dadurch könnte die definitive Ausrottung der Poliolähmung, mit den jährlichen Kosten von einer Billion Dollar/Jahr, in weitere Ferne rücken.

Erläuterung:

OPV= orale Polio Vakzine (Serotyp 1,2,3),die ursprüngliche   Vakzine,

cVDPVs= zirkulierende aus der OPV-Vakzine hervorgegangene Viren (meistens Serotyp 2)

mOPV2= monovalente Serotyp 2-Vakzine

Zusammenfassung und Übersetzung aus dem Artikel von Leslie Roberts veröffentlicht am 06.07.2018 in Science Vol. 361 Heft 6397:10-11

G.Ramadori

Hierarchy and „flat“ organisation:the american example of the FBI director

James Comey; A HIGHER LOYALTY 2018:156

No matter how „flat“ an organisation, there is a hierarchy, and everyone knows  what it is.Even if everyone in the room is wearing a hooded sweatshirt,ripped jeans,and flip-flops.Even if we are all sitting on beanbags eating trail mix and spitballing ideas on a whiteboard,if anyone in the room is  a boss or owner,everyone knows it.Someone in the room is“above“ the others,whether that rank is expilicit or not.

 

THE POLIO ENDGAME: SECURING A WORLD FREE OF ALL POLIOVIRUSES

1-Seit 1988 Verringerung der Zahl der Krankheitsfälle durch wildes Poliovirus von 350.000 in 125 endemischen Ländern auf 20 in 2 Ländern (2017,99%-Reduktion).

Dies bedeutet, dass etwa 16 Millionen Menschen unter den Folgen der Polio-induzierten Lähmung zu leiden gehabt hätten, wenn der Impfstoff nicht eingeführt worden wäre.

2-Heute lebt 80% der Weltbevölkerung in Ländern, die von der WHO als Polio-frei erklärt worden sind.

3-In Nigeria, Pakistan und Afganistan ist wild Polio heute noch endemisch. In Pakistan sind leider in den Jahren 2013/2014 mehr als 50 Mitarbeiter der Impforganisation und am 20 April 2016 7 Polizisten, die die Impfenden schützen sollten ermordet worden (1). Pakistan hat eine lange Grenze zu Afganistan und eine große Zahl von afganischen Bürgern ist nach Pakistan geflüchtet. Das pakistanische Institut für Migrationspolitik schätzt, dass es an der afganischen Grenze ca. 1.400.000 nicht registrierte Flüchtlinge während 1.543,536 registriert wurden (Stand 25 Februar 2016)(2)

4-Von den 3 Polio-Stämmen (1,2,3) wird heute nur noch wild Polio-Stamm1 festgestellt.

5-Auch in den noch endemischen Ländern werden immer mehr Kinder von der oralen Massen- Impfung erreicht (ORAL POLIOVIRUS VACCINE OPV).

6-Jedes Jahr werden mehr als 400 Mio Kinder mehrfach mit 2.2 Billionen Impfdosen geimpft.

7-die Impfung immunisiert das Kind und unterbricht auch die Weitergabe des Virus in der Gemeinschaft, mit dem ultimativen Ziel der Eradikation der Infektion

8- In seltenen Fällen kann das attenuierte Virus in dem Impfstoff die sog. Serotyp 2 -Vakzin-assozierte paralytische Poliomyelitis in den behandelten Kindern verursachen und kann zum Vakzine-derived zirkulierenden Poliovirus werden.Ca 40% der Vakzine-assozierten paralytischen Poliomyelitiden(ca 200 Fälle/Jahr) und 90% der Ausbrüche von zirkulierenden Vakzine-derived Polioviren der letzten 10 Jahre waren durch den Serotyp 2 der trivalenten OPV-Vakzine verursacht.

9- Es ist daher unbedingt erforderlich, dass die Anwendung der trivalenten OPV-Vakzine beendet wird.

10- Dieses Verfahren ist bereits eingeleitet worden und sollte stufenweise weiterlaufen.

11-Nach der Erklärung der Eradikation des Polio-Stammes 2 im September 2015 sind alle Länder ab der zweiten Hälfte April 2016 von dem trivalenten OPV-Impfstoff (alle Serotypen 1,2,3) zum bivalenten Impfstoff (Serotypen 1,3 aber nicht Serotyp 2) übergegangen.

 Alle 155 Länder der Welt haben innerhalb von 2 Wochen alle trivalenten OPV- Impfstoffe durch die bivalenten ersetzt. Dadurch sollte die Vakzine-assozierte Poliomyelitis nicht mehr vorkommen.

12-Da aber die Vollständigkeit des Überganges vom trivalenten in den bivalenten OPV in manchen Ländern nicht überprüft werden kann und ein Abfall der Immunität gegen den Serotyp 2 nicht immer

ausgeschlossen werden kann, ist ein weiteres Auftreten der Vakzine-induzierten (Stamm 2)-Poliomyelitis in der Zeit unmittelbar nach der Umstellung der OPV  nicht ausgeschlossen . In der Tat sind Serotyp 2-Fälle im Jahr 2016 (aber kein Fall in 2017) in Nigeria und in Pakistan gemeldet worden.

13-Neu Ausbrüche von zirkulierendem Vakzine-derived Serotyp 2-Poliovirus sind in Mai 2017 in Syrien (74 Fälle bis 27 Dez 2017) und in der Republik Congo (12 Fälle) festgestellt worden. Die Paralyse bei den 86 Kindern macht klar wie notwendig es ist, dass alle trivalenten Vakzinen zerstört werden und dadurch nicht mehr zur Anwendung kommen.

14-Als internationale Antwort auf diese Gefahr in der post-Switch-Era, werden OPV-2-Vakzine-Stocks bereitgehalten, um durch eine monovalente Impfung die Ausbrüche zu beenden. Diese Strategie wird in beiden Ländern derzeit praktiziert. Ähnlich ist in Syrien 2013-2014 vorgegangen worden, als ein Serotyp1-Ausbruch mit einer Serotyp-1 monovalenten Impfung, erfolgreich beendet werden konnte.

15-Um eine definitive Eradikation zu erreichen, ist es sehr wichtig, das Risiko von Laborfehlern zu minimieren und die Entdeckung, die Überwachung und Behandlung von immunsupprimierten Langzeitausscheidern, die eine Vakzine-assozierte paralytische Poliomyelitis hatten zu gewährleisten.

Das Ziel einer definitiven Eradikation kann nur erreicht werden, wenn alle Länder daran mitwirken

indem sie alle Stufen der Diagnostik, Prävention und Überwachung apparativ und personell unterstützen und umsetzen

Übersetzung aus dem Bericht in der Zeitschrift Lancet von G.Ramadori.

Autoren des Berichtes sind:

Michel Zaffran,Michael Mc Govern,Reza Hossaini,Rebecca Martin,Jay Wenger Lancet Vol 391, January 6,2018:11-13

Es wurden Angaben aus der Zeitschrift Ochsener Journal 2017 aus den Artikeln

1) Mahmood SU et al.Vol 17:13-14 und 2) Ullah MA und Husseini AM,2017,17:306

 

Diabetes type II,caloric overload and reversibility of insulin resistance

The number of persons (at any age) with this diagnose is increasing continously and the increase will become faster after the release of the iso-glucose as a chip sweetner into the european market.

It is therefore mandatory to make clear that diabetetes type II is not a real disease but a calorie-overload. It canbe compared with an overloaded truck.

The truck is functioning in an exceptional way if the loading prescription are respected. As most of the people diagnosed with type two diabetes are obese the consequence is fatty liver, increased glucose and trigliceryde but also insulin production and insulin serum level(insulin resistance).The consequence is also increased blood pressure.By reducing the daily caloric intake and the body weight blood glucose level will return to normal and the „disease“ will disappear.

The liver as the main organ in insulin resistance and metabolic syndrome

Salamah Mohammad Alwahsh and Giuliano Ramadori

The liver has a vital role in maintaining body energy homeostasis. Understanding the molecular mechanism of hepatic insulin resistance (IR) in obese and non-obese patients with non-alcoholic fatty liver disease (NAFLD) and diabetes is crucial for development of therapeutic strategies to maintain glucose homeostasis in these patients. MicroRNAs (miRs) are a class of single‑stranded noncoding RNAs that regulate the mRNA transcription or translation via specific mRNA complementary pairing of target genes. Emerging evidence suggests that miR-26a plays a key role in insulin signalling and is also known to play a critical role in tumorigenesis. Interestingly, Fu et al.(1) have demonstrated that hepatic miR-26a targets key genes involved in insulin signaling, fatty acid synthesis, and gluconeogenesis in humans and mice. miR-26a expression was reduced in the livers of an overweight human cohort and in high-fat-diet (HFD)-induced obese mice compared to controls. Conversely, restoring miR-26a in mice prevented obesity-associated metabolic damage (Fig.1A). These findings raise the possibility that hepatic miR-26a is a potential target for treatment of obesity and type II diabetes mellitus (T2DM).

To better understand the role of miR-26a, Fu et al. have studied its expression in different organs of obese (ob/ob) and lean mice. Interestingly, miR-26a expression was significantly downregulated in the livers of ob/ob mice compared to lean mice, while its expression was not changed in muscle, kidney and heart. Furthermore, the authors supported these findings in a range of models including human liver, two mouse transgenic models: globally overexpressed or liver-specific overexpression of miR-26a, HuH7 cells, and primary mouse hepatocytes.

Unlike miR-26a, the expression of miR-802 is increased in the liver of obese human subjects and obese mice. Compared to mouse isolated non-parenchymal cells, Kornfeld et al. found that the expression of miR-802 in primary hepatocytes was ten-fold higher, indicating that liver parenchymal cells represent the main source of miR-802 expression in this tissue(2). The authors also show that miR-802 targets Hnf1b in liver, causes glucose intolerance, impairs insulin signaling, and promotes hepatic gluconeogenesis. Overexpression of miR-802 in the murine hepatoma cell line Hepa1-6 resulted in a diminished ability of insulin to phosphorylate Akt; a central signaling node of its action. Whereas the hepatic overexpression of Hnf1b improves insulin sensitivity in Leprdb/db mice, indicating the critical role for miR-802- and Hnf1b-dependent regulation of hepatic IR and obesity-associated impairment of glucose metabolism(2).

Fu et al. found that the plasma and liver triglyceride levels and the expression of genes involved in β-oxidation and de novo lipogenesis were significantly lower in global overexpression of miR-26a transgenic (Hprt-Mir26a Tg ) mice fed a HFD compared to wild-type (WT), however, it would be interesting to know what the fate of the ingested fat is. This could provide a clue about the comparable animal’s body weight and whether the triglycerides were exported to the adipose tissues. In addition, levels of HDL-cholesterol were significantly reduced in Hepatocyte-specific miR-26a transgenic mice (Alb-Mir26a Tg) mice versus WT controls. It would be interesting to explore the pro-inflammatory cytokines, e.g., TNFα, as an important effector involved in IR(3), in the Alb-Mir26a Tg mice.

Several conditions are thought to participate in (hepatic) IR including the ingestion of alcohol, fructose, cholesterol, and high-fat-enriched diets. Other potential conditions include involvement of gut microbiota, oxidative stress and inflammation. Consumption of HFD leads to an accumulation of fat in the hepatocyte through the effect of insulin on the hepatocytes. It has to be hypothesized that as a result of long-term intake of high-fat and/or high-carbohydrate diet, followed by development of fatty liver, the insulin and glucose from the portal blood cannot be taken up any more by the fat loaded hepatocyte, underscoring the main role of the liver in insulin resistance.

Metformin, a drug of choice for the treatment of T2DM in overweight and obese patients, improves insulin sensitivity, thereby improving insulin potency, whilst also suppressing glucose production by the liver. Interestingly, metformin not only has a blood-glucose lowering effect, but it also protects against the development of fructose-induced steatosis in mice through mechanisms involving its direct effects on hepatic insulin signalling and changes in intestinal permeability. This may lead to endotoxin-dependent activation of hepatic Kupffer cells and inflammation. Indeed, treating mice with metformin (300 mg/kg BW/day) for 8 weeks protects against fructose-induced loss of the tight junction proteins occludin and zonula occludens-1 in the duodenum; consequently preventing the onset of NAFLD(6).

In line with these findings, rats fed on Lieber-DeCarli with alcohol and high-fructose developed metabolic syndrome, non-alcoholic steatohepatitis (NASH), and had increased hepatic neutrophils, and higher lipocalin-2 levels in liver and serum compared to  controls(4). In rats, the combination of alcohol and fructose in a high-fat-diet induced liver dysfunction, dyslipidemia, low-grade inflammation, and IR characterized by decreased gene expression of insulin receptor in the liver on one side and by hyperinsulinemia and normal c-peptide serum levels(5). Together, consumption of a HFD and fructose has either a direct effect to induce fatty liver and IR, or indirectly via enhancing the influx of gut microbiota/endotoxins to the liver. However, it is still not known whether the translocation of gut microbiome or microbial products is a prerequisite to develop hepatic steatosis and insulin unresponsiveness, since this has to be explored in ‘‘germ-free’’ mice, and fructose was shown to induce fat accumulation in hepatocytes in vitro without the need of inflammatory stimuli.

In a mouse model of methionine-choline deficient (MCD) diet, and ‘‘Western diet’’ (HFD plus high-corn fructose syrup), Machado et al. reported that Western diet mimics a metabolic profile associated with human NASH, namely hyperglycemia/IR and dyslipidemia, and causes massive hepatic steatosis, moderate inflammation and hepatomegaly. In contrast, MCD diet induced less hepatic steatosis, but more liver injury, e.g., fibrosis, oxidative stress and inflammation than the Western diet, and it did not induce hyperlipidemia/IR. This most probably indicates that hepatic steatosis can precede hepatic IR. Machado et al. however, excluded the microbiome effects in the development of NASH(8). In addition, adiponectin inhibits hepatic fibrosis by promoting binding of suppressor of cytokine signalling-3 to Ob-Rb (long form of the leptin receptor), and by stimulating protein tyrosine phosphatase-1B expression and activity, thus inhibiting JAK2/STAT3  pathway signalling at multiple points (Fig.1B)(7).

Until about 40 years ago diabetes mellitus was classified in juvenile and late onset. In the first case the diabetes was insulin deficient(type I) and in the second case it was insulin-resistant(typeII)(9).As childhood obesity  started to increase diabetes type II was no more considered late onset diabetes and this differentiation can now be considered obsolete.In fact

in the last 20 years the increment of obesity in childhood and adolescentce has been accompained by an increase of typeII diabetes in these group of young patients (10 ) as it has happened for adults.Together with obesity the developement of fatty liver disease (NAFLD) has also increased.

The liver plays a very important role in clearing insulin from the portal blood (11).By this way Insulin is responsible for metabolic homeostasis and growth not only in the liver but in the whole body (12)

It is therefore understandable that the liver plays a key role in regulating both glucose and lipid metabolism, derangements of which occur in NAFLD accompanied with T2DM. In T2DM, hyperglycemia coexisting with hyperinsulinemia (but with normal serum level of c-peptide) could result from disturbed function of the insulin receptor and/or of the insulin receptor substrate-I and -II resulting from the inability of the steatotic hepatocytes to take up and store glucose as glycogen after a meal. This leads to portal blood glucose and insulin bypassing the liver and reaching the systemic circulation.  Reduction of bodyweight by lifestyle changes and or by the administration of drugs like metformin or glucagon-like peptide-1-agonists is associated with reduced steatosis, augmented insulin, and glucose-uptake by the hepatocyte (improved IR) followed by reduction of hyperinsulinemia and of hyperglicemia (Fig.1B) in obese people with T2DM. Therefore, approaches such as induction of hepatic miR21a expression is worth evaluating as a potential therapy for obesity and T2DM.

References

 

  1. Fu X, Dong B, Tian Y, Lefebvre P, Meng Z, Wang X, Pattou F, et al. MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids. J Clin Invest 2015;125:1–13.
  2. Kornfeld JW, Baitzel C, Könner AC, Nicholls HT, Vogt MC, Herrmanns K, Scheja L, et al. Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 2013;494:111–115.
  3. Zhou L, Wang L, Yang B, Zeng J, Zhang Q, Lei H, Xu S. Protective effect of pretreatment with propofol against tumor necrosis factor-α-induced hepatic insulin resistance. Exp Ther Med 2015;10:289–294.
  4. Alwahsh SM, Xu M, Seyhan HA, Ahmad S, Mihm S, Ramadori G, Schultze FC. Diet high in fructose leads to an overexpression of lipocalin-2 in rat fatty liver. World J Gastroenterol 2014;20:1807–21.
  5. Alwahsh SM, Xu M, Schultze FC, Wilting J, Mihm S, Raddatz D, Ramadori G. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats. PLoS One 2014;9:e104220.
  6. Spruss A, Kanuri G, Stahl C, Bischoff SC, Bergheim I. Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function. Lab Investig 2012;92:1020–1032.
  7. Handy JA, Fu PP, Kumar P, Mells JE, Sharma S, Saxena NK, Anania FA. Adiponectin inhibits leptin signalling via multiple mechanisms to exert protective effects against hepatic fibrosis. Biochem J 2011;440:385–395.
  8. Machado MV, Michelotti GA, Xie G, de Almeida TP, Boursier J, Bohnic B, Guy CD, et al. Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease. PLoS One 2015;10:e0127991.
  9.   Raddatz D, Ramadori G.  Carbohydrate metabolism and the liver: actual aspects from physiology and disease.Z Gastroenterol. 2007 Jan;45(1):51-62. Review.

  10. Boney CharlotteM, et al.:Metabolic Syndrome in Childhood:Association with Birth weight,Maternal Obesity and Gestational Diabetes Mellitus.Pediatrics2005;115:e290-e296
  11. Tofolo G et al.:A minimal modelof insulin secretion and kinetics to  assess  hepatic insulin extraction.Am J Physiol Endocrinol Metab 2006;290:e169–e176
  12. Griffen SC at al.Insulin exerts metabolic and growth-promoting effects by a directaction on the liver  in vivo:Clarification of the functional significance of the portal vascular  link between the beta cells  of the pancreatic ilsets and the liver.Proc Natl Acad Sc 1987;84:7300-7304
  13. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.

    Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI.

    J Biol Chem. 2004 Jul 30;279(31):32345-53.

    PMID:
    15166226

    Free Article

  14. nsulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance.

    Petersen MC, Madiraju AK, Gassaway BM, Marcel M, Nasiri AR, Butrico G, Marcucci MJ, Zhang D, Abulizi A, Zhang XM, Philbrick W, Hubbard SR, Jurczak MJ, Samuel VT, Rinehart J, Shulman GI.

    J Clin Invest. 2016 Nov 1;126(11):4361-4371. doi: 10.1172/JCI86013.

    PMID:
    27760050

 

 

 

 

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How to find out the „Truth“

When you visit Pompei, you first come into a large square  before you enter the old town.This was the „agora“ of the ancient greeks.It was the square where to go to discuss  and exchange opinions.According to the greek philosophers,this was considered to be the best way to find out the truth.

I went to Boston in october 1984 to spend a period of research at the division of cell and molecolar biology in the Enders Building  of The Children´s Hospital at Harvard Medical School. After having established the method of isolating liver cells and short-term cultures I wanted to study the intracellular steps of protein synthesis and its modulation by cytokines.The chief of the large and crowded laboratory,dr Harvey Colten ,also chief of pneumology, used to reside in a small office,where everybody working in the lab could visit him and discuss with him the most recent experiments and the latest „fresh“ results.By entering the office,one would immediately look at a small brownish sign on the wall and reed, written in yellow capital letters, the question „HOW DO YOU KNOW“. The task of the everyday work was to generate reproducible results which could allow to drow conclusions which could have been published and eventually reproduced in other laboratories around the world.

It makes me very sad to hear that in the same country now fake news agencies are becoming a big business.

CONFLICT OF INTEREST IN CLINICAL MEDICINE

 

As medical progress continues to develop and medical diagnostic and medical treatments cause higher costs ,there is an urgent need to comment new developements in medical basic  research and in clinical point of view .As clinical decisions have to be fast and faster and economic pressure increases continously there is less and less room for jung doctors to observe the response of their treatment approaches in both conservative and surgical medicine.For this reason economy may become a very important (hidden) variable in treatment flow sheets. A new definition of „conflict of interest“ should be discussed by ethical committees.