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
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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.