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Diabetes, Type II

Diabetes manifests itself when insulin production is not sufficient to keep blood sugar levels within the normal range, both after meals and in the periods between meals. In type 2 diabetes there is almost always a reduced response to insulin in the tissues (insulin resistance) in addition to a reduced capacity to produce insulin by the pancreatic beta-cells.

Symptoms

The process of development of diabetes takes years. The effects of manifest diabetes can go unnoticed by the patient for a long time and in general about half of the diabetic population in Western societies are undiagnosed. (ref) A visual sign that one is at high risk for diabetes is an elevated waist-hip ratio. Symptoms of established diabetes are increased thirst, increased urinary volume, weight loss, lethargy and increased suceptibility to infections. Later symptoms of untreated diabetes include ketoacidosis, stomach pain, vomiting and coma.

Major long term symptoms and effects of diabetes include retinopathy, neuropathy, nephropathy, congitive dysfunction, foot sores and amputations of limbs.

Management

Diet and exercise are the traditional lifestyle interventions used to prevent and treat type 2 diabetes. Different components of the diet can affect the course of type 2 diabetes, but a low carbohydrate diet appears to be giving the most significant results. 1) 2) 3) Both endurance and resistance exercise yield improvements in many aspects of the metabolic derangements in diabetes type II.4)

Sulfonylureas, biguanids, glitazones, GLP-1 analogs, DPP-4 inhibitors and insulin are the main medication groups used to treat type 2 diabetes. These medications have modulation of insulin funcion, increments in insulin sensitivity and increments in insulin production as their main mechanisms of action.

Recent Research

Prevention of microalbuminuria in patients with type 2 diabetes and hypertension. 5)

Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes. 6)

Evidence of infectious cause

Description: http://www.nature.com/nrendo/journal/v8/n1/full/nrendo.2011.192.html?WT.ec_id=NRENDO-201201

Diabetologia. 2011 Dec;54(12):3055-61.Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept.

Amar J, Serino M, Lange C, Chabo C, Iacovoni J, Mondot S, Lepage P, Klopp C, Mariette J, Bouchez O, Perez L, Courtney M, Marre M, Klopp P, Lantieri O, Doré J, Charles MA, Balkau B, Burcelin R; D.E.S.I.R. Study Group.

Source: Inserm U1027, University Paul Sabatier, CHU, Hôpital Rangueil, Avenue Jean Pouhles, Toulouse, France. amar.j@chu-toulouse.fr

Abstract

AIMS/HYPOTHESIS:

Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population.

METHODS:

Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) is a longitudinal study with the primary aim of describing the history of the metabolic syndrome. The 16S rDNA concentration was measured in blood at baseline and its relationship with incident diabetes and obesity over 9 years of follow-up was assessed. In addition, in a nested case-control study in which participants later developed diabetes, bacterial phylotypes present in blood were identified by pyrosequencing of the overall 16S rDNA gene content.

RESULTS:

We analysed 3,280 participants without diabetes or obesity at baseline. The 16S rDNA concentration was higher in those destined to have diabetes. No difference was observed regarding obesity. However, the 16S rDNA concentration was higher in those who had abdominal adiposity at the end of follow-up. The adjusted OR (95% CIs) for incident diabetes and for abdominal adiposity were 1.35 (1.11, 1.60), p = 0.002 and 1.18 (1.03, 1.34), p = 0.01, respectively. Moreover, pyrosequencing analyses showed that participants destined to have diabetes and the controls shared a core blood microbiota, mostly composed of the Proteobacteria phylum (85-90%).

CONCLUSIONS/INTERPRETATION:

16S rDNA was shown to be an independent marker of the risk of diabetes. These findings are evidence for the concept that tissue bacteria are involved in the onset of diabetes in humans.

Comment in Diabetes: tissue bacteria predict diabetes onset. [Nat Rev Endocrinol. 2011]

PMID: 21976140

NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | JANUARY 2012

Nature Reviews Endocrinology 8, 3 (2012); published online 8 November 2011; doi:10.1038/nrendo.2011.192

RESEARCH HIGHLIGHTS

The presence of bacterial components in blood predicts the onset of diabetes mellitus in a large general population, a study in Diabetologia shows. Amar and colleagues studied the ability of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes mellitus and obesity in a longitudinal study cohort of 3,280 healthy adults aged 30–65 years at baseline. “We studied the 16S rDNA gene, as it is highly conserved between different species of bacteria and is, hence, considered to be a marker of the overall crobiota,” recounts lead author Jacques Amar from the Centre Hospitalier Universitaire in Toulouse, France. The investigators determined the concentration of 16S rDNA in blood at baseline and assessed its relationship with incident diabetes mellitus and obesity over a follow-up period of 9 years. Furthermore, bacterial ylotypes in blood were identified by pyrosequencing of the overall 16S rDNA gene content in a nested case–control study.

DIABETES

Tissue bacteria predict diabetes onset Amar et al. showed 16S rDNA to be an independent marker of diabetes risk, as the burden of bacteria, mainly the gram-negative proteobacteria, in blood predicted disease onset. such association was found with obesity. “Beyond the role of gut microbiota, these results shift the focus to tissue microbiota,” says Amar. The results also add credence to the previously reported causative and predictive roles of lipopolysaccharides in the onset of diabetes mellitus. “These data support the involvement of low-grade chronic infection in the onset of metabolic diseases,” concludes Amar, “and open the way for the development of new biomarkers and therapeutic strategies in the field of metabolic diseases and their complications.” Linda Koch

Original article Amar, J. et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia doi:10.1007/s00125-011-2329-8

© 2011 Macmillan Publishers Limited. All rights reserved

To what extent microbes contribute to the global diabetes burden, and to what extent antimicrobial therapy can prevent or reverse the disease, has to a limited degree been investigated in clinical trials (see below). However, the finding that obese and diabetic patients have higher levels of lipopolysaccharides (LPS, a bacterial product) in their bodies and that insulin level is correlated with the amount of LPS make a strong argument for infectious cause.7) Inflammation (which is intimately associated with infection) induced by cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. 8) 9) 10) leads to insulin resistance. Abrogation of inflammation ameliorates insulin resistance. 11) 12) 13) 14) Deletion of the insulin receptor in myeloid cell lines inhibits development of insulin resistance.15)

Further, beta amyloid, which has been identified as an antimicrobial peptide,16) is found in increased amounts in pancreatic beta cells of type 2 diabetics,17) hinting at the presence of microorganisms as a cause of the malfunction and destruction of the beta cells.

“The VDR is responsible for expression of the Insulin receptor substrate (reference needed). Fix the VDR dysfunction and you will stymy the diabetes. In addition, those of our members who have had high blood-glucose levels have not suffered from having those high BG levels to the same extent that a 'normal' individual would have done, as the VDR activation, and the Angiotensin receptor blockade, both produced by the Olmesartan, have protected their bodies from the expected damage.” Trevor Marshall

Antimicrobial therapy in insulin resistance/type 2 diabetes

Helicobacter pylori eradication led to a reduction in insulin resistance18). The use of oxytetracycline in obese mice reduced insulin resistance19)

Diabetes can cause a sugar coating that smothers body's immune defences

http://www.eurekalert.org/pub_releases/2010-08/uow-dcc082210.php

The researchers looked at the similarities in chemical structure between glucose in blood and body fluids, and two other sugar called mannose and fucose. These sugars are found on the surfaces of bacteria and fungi and act as targets for receptors in our body that have evolved to detect and bind to microbial sugars to then combat the infection.

The research found that high levels of glucose outcompetes the binding of mannose and fucose to the specialized immune receptors, potentially blocking these receptors from detecting infectious bacteria and fungi. Glucose also binds in such a way that it inhibits the chemical processes that would normally then follow to combat infections. If this happens it can inhibit a range of key processes including: • It can inhibit the function of immune system receptors called C-type lectins such as MBL (Mannose-binding lectin) which are known to bind to a sugar known as mannose that is present in the structure of infectious fungal bacterial cell walls. Unlike glucose, mannose does not exist in mammals as a free sugar in the blood.

• The loss of MBL function may also predispose the body to chronic inflammatory diseases, since MBL is involved in the processing and clearance of apoptotic cells (dying cells).

• A number of C-type lectins tat can be affected by raised glucose levels, including MBL, but also including immune cell surface receptors DC-SIGN and DC-SIGNR, are found in key parts of our circulation and vascular system such as plasma, monocytes, platelets and endothelial cells that line blood vessels. Inhibiting the function of these key molecules in those settings could contribute to diabetic cardiovascular and renal complications.

Warwick Medical School researcher Dr Daniel Mitchell said:

“Our findings offer a new perspective on how high glucose can potentially affect immunity and thus exert a negative impact on health. It also helps to emphasize the importance of good diet on preventing or controlling diseases such as diabetes. We will build on these ideas in order to consolidate the disease model and to investigate new routes to treatment and prevention.”

60. Rayfield EJ, Kelly KJ, Yoon JW. Rubella virus-in- duced diabetes in the hamster. Diabetes. 1986;35:1278-1281. 61. Menser MA, Forrest JM, Bransby RD. Rubella in- fection and diabetes mellitus. Lancet. 1978;1:57-60. 62. Ramsingh AI, Chapman N, Tracy S. Coxsackieviruses and diabetes. Bioessays. 1997;19:793-800.

Burden of Infection and Insulin Resistance in Healthy Middle-Aged Men

Helicobacter pylori Infection Significantly Increases Insulin Resistance in the Asymptomatic Japanese Population

 	
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Author(s): Gunji T (Gunji, Toshiaki)2, Matsuhashi N (Matsuhashi, Nobuyuki)1, Sato H (Sato, Hajime)3, Fujibayashi K (Fujibayashi, Kazutoshi)2, Okumura M (Okumura, Mitsue)2, Sasabe N (Sasabe, Noriko)2, Urabe A (Urabe, Akio)2 Source: HELICOBACTER Volume: 14 Issue: 5 Pages: 144-150 Published: OCT 2009 Times Cited: 1 References: 44 Citation Map Abstract: Background: Helicobacter pylori infection has been shown to contribute to atherosclerosis and cardiovascular diseases. Insulin resistance is the pathophysiologic background of the clinical features of atherosclerosis and cardiovascular diseases. We examined the association between H. pylori infection and insulin resistance in a large Japanese population. Materials and Methods: Fifteen hundred ninety-eight consecutive asymptomatic subjects that underwent a complete medical survey in our institute between May 2007 and July 2008 were recruited. Cases under medication for hypertension, hyperlipidemia, diabetes mellitus, hyperuricemia, or cardiovascular diseases were excluded from the study. Cases suffering from chronic renal or liver failure were also excluded. The homeostasis model assessment of insulin resistance (HOMA-IR) score was used to quantitatively estimate insulin resistance. Visceral and subcutaneous adipose tissues (SAT) were measured by computed tomography. The association between H. pylori serostatus and HOMA-IR score was investigated by multivariate regression analysis. Results: A total of 988 men and 119 women were eventually eligible for this cross-sectional survey. Helicobacter pylori seropositivity was significantly higher in 99 cases with insulin resistance (HOMA-IR >= 2.5) compared with 1008 cases without insulin resistance (HOMA-IR < 2.5) (39.4 vs 28.7%, p = .027). There was a significant association between H. pylori serostatus and HOMA-IR score by multiple linear regression analysis (coefficients = 0.152, 95% CI = 0.058-0.246, p = .001), after adjusting for sex, age, body mass index, waist girth, visceral and subcutaneous adipose tissues, smoking status, alcohol consumption, dietary habits, and physical activity. Conclusions: Helicobacter pylori infection significantly and independently contributed to promoting insulin resistance in a large asymptomatic population.

Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E740-7. Epub 2006 Nov 7. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S.

Diabetes and Metabolism Research Laboratories, Clinical Sciences Research Institute, Warwick Medical School, Clinical Sciences Bldg., University Hospital Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, West Midlands, UK. Abstract Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-kappaBA protein that stimulates the release of inflammatory cytokines in response to infection in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold (P<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-alpha and IL-6 secretion (IL-6, Control: 2.7+/-0.5 vs. LPS: 4.8+/-0.3 ng/ml; P<0.001; TNF-alpha, Control: 1.0+/-0.83 vs. LPS: 32.8+/-6.23 pg/ml; P<0.001). NF-kappaB inhibitor reduced IL-6 in AbdSc adipocytes (Control: 2.7+/-0.5 vs. NF-kappaB inhibitor: 2.1+/-0.4 ng/ml; P<0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF-kappaB was increased in T2DM patients (P<0.05), and TLR-2, TRAF-6, and NF-kappaB were increased in LPS-treated adipocytes (P<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, P<0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P=0.0395) and serum LPS (reduced by 35%, P=0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease.. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.

PMID: 17090751

Diabetes. 2010 Jan;59(1):161-71. Epub 2009 Sep 30. Tetracycline treatment retards the onset and slows the progression of diabetes in human amylin/islet amyloid polypeptide transgenic mice. Aitken JF, Loomes KM, Scott DW, Reddy S, Phillips AR, Prijic G, Fernando C, Zhang S, Broadhurst R, L'Huillier P, Cooper GJ.

School of Biological Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Abstract OBJECTIVE: Aggregation of human amylin/islet amyloid polypeptide (hA/hIAPP) into small soluble beta-sheet-containing oligomers is linked to islet beta-cell degeneration and the pathogenesis of type 2 diabetes. Here, we used tetracycline, which modifies hA/hIAPP oligomerization, to probe mechanisms whereby hA/hIAPP causes diabetes in hemizygous hA/hIAPP-transgenic mice.

RESEARCH DESIGN AND METHODS: We chronically treated hemizygous hA/hIAPP transgenic mice with oral tetracycline to determine its effects on rates of diabetes initiation, progression, and survival.

RESULTS: Homozygous mice developed severe spontaneous diabetes due to islet beta-cell loss. Hemizygous transgenic animals also developed spontaneous diabetes, although severity was less and progression rates slower. Pathogenesis was characterized by initial islet beta-cell dysfunction followed by progressive beta-cell loss. Islet amyloid was absent from hemizygous animals with early-onset diabetes and correlated positively with longevity. Some long-lived nondiabetic hemizygous animals also had large islet-amyloid areas, showing that amyloid itself was not intrinsically cytotoxic. Administration of tetracycline dose-dependently ameliorated hyperglycemia and polydipsia, delayed rates of diabetes initiation and progression, and increased longevity compared with water-treated controls.

CONCLUSIONS: This is the first report to show that treating hA/hIAPP transgenic mice with a modifier of hA/hIAPP misfolding can ameliorate their diabetic phenotype. Fibrillar amyloid was neither necessary nor sufficient to cause diabetes and indeed was positively correlated with longevity therein, whereas early- to mid-stage diabetes was associated with islet beta-cell dysfunction followed by beta-cell loss. Interventions capable of suppressing misfolding in soluble hA/hIAPP oligomers rather than mature fibrils may have potential for treating or preventing type 2 diabetes.

PMID: 1979406

Neurobiol Aging. 2010 Sep;31(9):1503-15. Epub 2008 Oct 23. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Miklossy J, Qing H, Radenovic A, Kis A, Vileno B, Làszló F, Miller L, Martins RN, Waeber G, Mooser V, Bosman F, Khalili K, Darbinian N, McGeer PL.

Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada. judithmiklossy@bluewin.ch Abstract Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (Abeta) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated Abeta, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. Abeta was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that Abeta deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that Abeta deposits and hyperphosphorylated tau may also occur in other organs than the brain.

PMID:18950899

Diabetologia. 2011 Dec;54(12):3055-61.Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Amar J, Serino M, Lange C, Chabo C, Iacovoni J, Mondot S, Lepage P, Klopp C, Mariette J, Bouchez O, Perez L, Courtney M, Marre M, Klopp P, Lantieri O, Doré J, Charles MA, Balkau B, Burcelin R; D.E.S.I.R. Study Group. Source Inserm U1027, University Paul Sabatier, CHU, Hôpital Rangueil, Avenue Jean Pouhles, Toulouse, France. amar.j@chu-toulouse.fr Abstract

AIMS/HYPOTHESIS:

Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population.

METHODS:

Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) is a longitudinal study with the primary aim of describing the history of the metabolic syndrome. The 16S rDNA concentration was measured in blood at baseline and its relationship with incident diabetes and obesity over 9 years of follow-up was assessed. In addition, in a nested case-control study in which participants later developed diabetes, bacterial phylotypes present in blood were identified by pyrosequencing of the overall 16S rDNA gene content.

RESULTS:

We analysed 3,280 participants without diabetes or obesity at baseline. The 16S rDNA concentration was higher in those destined to have diabetes. No difference was observed regarding obesity. However, the 16S rDNA concentration was higher in those who had abdominal adiposity at the end of follow-up. The adjusted OR (95% CIs) for incident diabetes and for abdominal adiposity were 1.35 (1.11, 1.60), p = 0.002 and 1.18 (1.03, 1.34), p = 0.01, respectively. Moreover, pyrosequencing analyses showed that participants destined to have diabetes and the controls shared a core blood microbiota, mostly composed of the Proteobacteria phylum (85-90%).

CONCLUSIONS/INTERPRETATION:

16S rDNA was shown to be an independent marker of the risk of diabetes. These findings are evidence for the concept that tissue bacteria are involved in the onset of diabetes in humans.

Comment in

Diabetes: tissue bacteria predict diabetes onset. [Nat Rev Endocrinol. 2011]

PMID: 21976140 [

NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | JANUARY 2012

Nature Reviews Endocrinology 8, 3 (2012); published online 8 November 2011; doi:10.1038/nrendo.2011.192

RESEARCH HIGHLIGHTS

The presence of bacterial components in blood predicts the onset of diabetes mellitus in a large general population, a study in Diabetologia shows.

Amar and colleagues studied the ability of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes mellitus and obesity in a longitudinal study cohort of 3,280 healthy adults aged 30–65 years at baseline. “We studied the 16S rDNA gene, as it is highly conserved between different species of bacteria and is, hence, considered to be a marker of the overall microbiota,” recounts lead author Jacques Amar from the Centre Hospitalier Universitaire in Toulouse, France.

The investigators determined the concentration of 16S rDNA in blood at baseline and assessed its relationship with incident diabetes mellitus and obesity over a follow-up period of 9 years.

Furthermore, bacterial phylotypes in blood were identified by pyrosequencing of the overall 16S rDNA gene content in a nested case–control study.

DIABETES

Tissue bacteria predict diabetes onset Amar et al. showed 16S rDNA to be an independent marker of diabetes risk, as the burden of bacteria, mainly the gram-negative proteobacteria, in blood predicted disease onset. No such association was found with obesity.

“Beyond the role of gut microbiota, these results shift the focus onto tissue microbiota,” says Amar. The results also add credence to the previously reported causative and predictive roles of lipopolysaccharides in the onset of diabetes mellitus.

“These data support the involvement of low-grade chronic infection in the onset of metabolic diseases,” concludes Amar,“and open the way for the development of new biomarkers and therapeutic strategies in the field of metabolic diseases and their complications.”

Linda Koch

Original article Amar, J. et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia doi:10.1007/s00125-011-2329-8

© 2011 Macmillan Publishers Limited. All rights reserved

Notes and comments

<DiseaseHierarchy>

  • s174:

Parathyroid Hormone and Th1 inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.

“1,25-D spreads from the site of the inflammation (where it is acting as a cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system.) through the bloodstream (acting as a hormone)… 1,25-D directly controls the Parathyroid Hormone (PTH) and thence the Thyroid hormones as well as a number of other metabolic pathways, so it is pretty powerful feedback to the body systems, and when the bacteria interrupt that feedback path everything goes unstable (that's how a control-systems engineer might describe it).”

..Trevor..

s177, s178: Read first: 20)

http://www.ncbi.nlm.nih.gov/pubmed/19225551

egg consumption and diabetes21)

Diabet Med. 2009 Feb;26(2):149-52. Serological evidence of infections and Type 2 diabetes: the MultiEthnic Study of Atherosclerosis. Lutsey PL, Pankow JS, Bertoni AG, Szklo M, Folsom AR.

Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. lutsey@umn.edu Abstract AIMS: Prospective studies have identified chronic inflammation as a risk factor for Type 2 diabetes. However, it is not known whether infection by specific pathogens or having a greater 'pathogen burden' is associated with diabetes. The aim of this study was to examine the cross-sectional relation of seropositivity to five pathogens (Chlamydia pneumoniae, cytomegalovirus, Helicobacter pylori, hepatitis A virus, herpes simplex virus) and prevalent diabetes. METHODS: Baseline data from a random sample of MultiEthnic Study of Atherosclerosis (MESA) participants (n = 1000; age 45-84 years) were used. Diabetes was defined by American Diabetes Association 2003 criteria, and 'pathogen burden' by the number of pathogens (0-5) for which an individual was seropositive. Logistic regression was used to test differences in diabetes prevalence by seropositivity. Linear regression was used to explore associations between pathogen seropositivity and the inflammation markers C-reactive protein, interleukin-6 and fibrinogen. RESULTS: Diabetes prevalence was 12.7%, whereas seropositivity for C. pnuemoniae was 76%, cytomegalovirus 77%, H. pylori 45%, hepatitis A 58% and herpes simplex virus 85%. Seventy-two percent were seropositive for three or more pathogens. In crude analyses, the prevalence of diabetes was higher among those with a pathogen burden of three or more, and with seropositivity to cytomegalovirus, H. pylori, hepatitis A and herpes simplex virus. After adjustment for demographic covariates (particularly race), all associations became non-significant. Pathogen seropositivity was also not related to inflammation marker levels. CONCLUSIONS: Following demographic adjustments, no associations were observed between infection by several pathogens and diabetes status, suggesting no aetiological role for them in the occurrence of diabetes.

PMID: 19236617

10 Kramer, Hilary. “Diabetes is Killing our Economy”. Forbes.com. 13 Jan 2010. <http://www.forbes.com/2010/01/13/kramer-obesity-nutrition-intelligent-investing-diabetes.html>;

Nestle Nutr Workshop Ser Clin Perform Programme. 2006;11:139-50; discussion 150-3. Links The accelerator hypothesis: a unifying explanation for type-1 and type-2 diabetes.

Wilkin TJ. Department of Medicine, Postgraduate Medical School, Derriford Hospital, Plymouth, UK. Despite 30 years of research, the cause of type-1 diabetes remains unknown. Meanwhile, its incidence has risen three-fold, its clinical features have become increasingly difficult to distinguish from type-2 diabetes and the contribution of genes to its pathogenesis has changed. The accelerator hypothesis argues that type-1 and type-2 diabetes are the same disorder of insulin resistance set against different genetic backgrounds. It identifies three processes which variably accelerate beta cell loss: constitution, insulin resistance and the immune response to it. None of the accelerators leads to diabetes in the absence of weight gain, a trend which the hypothesis deems central to the rising incidence of all diabetes in the industrially developed and developing world. Weight gain causes an increase in insulin resistance, which results in the weakening of glucose control. The rising blood glucose accelerates beta cell apoptosis (glucotoxicity) and, by increasing beta cell immunogenicity, further accelerates apoptosis in a subset genetically predisposed to an intense immune response. Rather than overlap between the two types of diabetes, the accelerator hypothesis envisages overlay–one a subset of the other. Body mass is central to the development and rising incidence of all diabetes. Only tempo distinguishes type 1 from type 2. The control of weight gain, and with it insulin resistance, could be the means of preventing both by slowing their progression. PMID: 16820737

Infectious cause of diabetes

Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy.

The association of metabolic syndrome and Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus type 1: the Persian Gulf Healthy Heart Study.

Diabetes clusters suggest infectious cause

Thu Jul 13, 2005

NEW YORK (Reuters Health) - Results of a new study support the notion that common infections may trigger type 1 diabetes in children and young adults.

Specifically, UK researchers uncovered evidence of clustering among young diabetes patients.

A relative high number of cases in a small area and within a limited period – space-time clustering –is “consistent” with an environmental component in disease development, “possibly linked to infections,” Dr. Richard J. Q. McNally, of the University of Newcastle upon Tyne, and colleagues explain in the journal Diabetologia.

The team used data from a population-based register in Yorkshire to look for evidence of space-time clustering of diabetes among subjects younger than age 30.

Included in the analysis were two data sets of patients diagnosed with type 1 diabetes: 3019 children up to 14 years of age who resided in Yorkshire between 1978 and 2002; and 989 patients between 15 and 29 years who resided in West Yorkshire between 1991 and 2002.

In the first group, significant space-time clustering, based on place and time of diagnosis, was confirmed for the children between 10 and 14 years old. In the second group, space-time clustering was observed for those between 15 and 19 years old.

“These findings suggest that infections may precipitate type 1 diabetes in a limited number of susceptible people,” McNally commented to Reuters Health. “Other environmental factors are also likely to be involved.”

Although the findings suggest an environmental cause, the investigators note that the study cannot confirm if the environmental effects are direct or if they merely unmask latent diabetes.

SOURCE: Diabetologia, July 2006.

BCG vaccine and diabetes

It is well documented, over several decades, that the BCG vaccine causes Sarcoidosis, eg “Juvenile sarcoidosis after BCG vaccination (2006)” http://www.ncbi.nlm.nih.gov/pubmed/12734491

“Juvenile sarcoidosis after BCG vaccination (1989)” http://www.ncbi.nlm.nih.gov/pubmed/2602688

“Incidence of Intrathoracic Sarcoidosis among young adults participating in a trial of Tuberculosis vaccines (1965)” http://www.ncbi.nlm.nih.gov/pubmed/14321221

The use of BCG vaccine has been banned in several countries , as being unsafe. Its use in Diabetes is not even a new idea, having been first mooted in 1991 http://www.ncbi.nlm.nih.gov/pubmed/1833072

Anybody who is researching the use of live vaccines, and who doesn't know about the terrible track record of BCG, needs to have their researchers' licenses stripped from them, in my opinion. ..Trevor..

See also Infections linked to Type 1 diabetes

Last edited on Mon Mar 17th, 2008 15:22 by

Barb: Dx Inflammatory Disease Endocrine Imbalance 2003| 24+ years not Dx| MP Aug04| ABC of MP| MP Search| Aussie Barb Research Team

Joined: Thu Jul 22nd, 2004 Location: Australia Posts: 19485 Status: Offline

Posted: Tue Jun 14th, 2005 15:36 

(filelink) Diabetes and the Marshall Protocol

I have no data whether the damage causing Type 1 diabetes can be reversed. Certainly it will take a long time for the body's normal insulin production to start up again. ..Trevor..

How much resolution of your type I diabetes you will achieve on the MP is impossible to say since this is relatively uncharted territory. You will want to follow your doctors recommendations for monitoring your blood sugar levels.

ImmunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed. may reveal inflammation in delicate tissues that are commonly damaged by high blood sugar and high insulin levels. Therefore, your doctor may want to monitor your kidney function, liver enzymes and eye inflammation. He will know what tests to order. You can expect some exacerbation of inflamed tissues and may see some labwork temporarily elevated. Adjusting the MP medications to reduce the Herx reactions will keep the inflammation under control.

See BENICAR AMELIORATES INSULIN RESISTANCE

Here is good news for those who are looking for recovery from Type 1 Diabetes: Insulin cells persist in long-standing diabetes by Megan Rauscher

I have suspected that recovery was possible right from my early days studying Diabetes in the early 80s, and it is nice to see studies which confirm my suspicion ..Trevor..

We are confident that benicar, plus the 1,2 and 3 abx combos we now have available, will get all of the species, or at least enough to get a patient to 'cure.' But different folks have different species dominant, and will need slightly different abx combos as they progress through the MP.

..Trevor..

s176:

Member's with diabetes

Interview with Chris Eastlund, a long-time MPer who has now essentially recovered from diabetes, sarcoidosis, and irritable bowel syndrome thanks to the MP.

captkirk: Bree: summary of improvements: A1C, weight, hearing etc

44 years of Diabetes Debbie Y

rc45guy: Type1 Diabetes Jan89, insulin pump, improvements.

Reported lapse in Benicar blockade results in ocular hemorrhage

-I was on prednisone for two years before starting the MP. Before I was on prednisone, I had little to no retinopathy. In the timespan of those two years on prednisone, I went from little to severe.

I had a hemmorhage in my right eye about 6wks ago. I was very lax in taking my Benicar over a period of 2 days (like twice a day, 16h apart), and on the 2nd day I got the hemmorhage.

It wasn't a conscious risk, I was 4h away from the hotel and my wife didn't have her normal purse carrying it. A total mistake on my part - not making that one again!

-I am a MPer in phase 3 who is on an insulin pump and have had diabetes type 1 for 46 years. My blood sugar levels have consistently dropped on the day I take my Z and for a few days after. Several things have changed since being on the MP: I can feel my hypoglycemia more now where before MP I could not feel any signs of hypoglycemia due to longstanding diabetes, at times I have had unexplained high glucose levels for no reason other than an IP event and taking extra Benicar straightened it out, my A1C has lowered to normal when it had not been for awhile, I have had no diabetic problems with my eyes since on antibiotics and Benicar, I have had no diabetic problems with infections and or healing. Taking the antibiotics and Benicar, along with the proper diabetic diet, checking glucose levels regularly and recording them and having regular A1C levels checked, have helped my diabetes status and has allowed me to see the effects from the MP meds. ~debbie y

s175:

Tests to monitor diabetes

Please see Suggested tests to monitor your progress on the MP.

You will want to monitor serum glucose levels at home. Doc will test HbA1C periodically.

s181:

Pancreatic transplants have high failure rate

I just attended a conference on Autoimmune Clinical Research and one of the papers was on Diabetes Type 1. It was reporting failures of pancreatic transplants, as they lost the ability to generate insulin after about 7 months.

The speaker was very insistent that this was due to an unknown cause, as they specifically looked to make sure (by biopsy) that there was no organ rejection. When they showed the biopsy slides with monocytes invading the new pancreas I knew we had a winner here

The monocytes had started to infiltrate the new pancreas by about 7 months, which is a very similar time to that it takes for granuloma to start to form in lungs transplanted into Sarc patients (granuloma are 90% monocytes). Glycogen was still being accreted by the islet cells, but the insulin secretion had already shut down.

..Trevor..

s180:

Eye problems are common in diabetics

The renin-angiotensin-aldosterone system and the eye in diabetes. http://tinyurl.com/67ldp

Immuno-localization of the calcitriol receptor, calbindin-D28k and the plasma membrane calcium pump in the human eye. http://tinyurl.com/552tv

Retinopathy

Retinopathy, in general, is a very common occurrence in Type 1 Diabetics, many of whom end up blinded by it.

A similar process, macular degeneration, is an inflammatory process (see http://tinyurl.com/yjthzk ).

Reduction of retinopathy during the course of the MP (in others) would tend to indicate it is also an inflammatory process. However, several of my Diabetes-research colleagues were convinced it was caused by the body failing to assimilate exogenous insulin correctly. see diagram summarizing some of the key relationships between the body's hormones and 1,25-D. You can access it at http://autoimmunityresearch.org/hormones.pdf

Be careful of the lasers. Th1 tissues don't heal as easily, and certainly not when a lot of incident radiation has been focused on them (excess Vit D production).

There is no effective treatment for Diabetic Retinopathy, so I would doubt that it “could be prevented with early detection.” I would like to see real data to back up that assertion

Peripheral blood vessels are profoundly affected during Th1 diseaseAny of the chronic inflammatory diseases caused by bacterial pathogens., usually by increased vascular permeability, but I am not sure how that translates to the retina. Blood flow takes a while to return to normal, maybe 3-5 years, depending on how sick you were in the first place.

The disease mechanisms are complex, I wouldn't even venture to fully characterize them. Blood flow is a very small part of it, as the changes that influence blood flow are the critical factors.

Dr. Trevor Marshall, Ph.D

See Pubmed: a common antibiotic called minocycline may slow or prevent diabetic retinopathy

Members' experiences

-I am a type 1 diabetic on MP, on an insulin pump. I have had DM for 46 years. Since being on MP, I have not experienced any negative issues with my diabetes. In fact, my A1C has improved, my eyes show no signs of retinopathy and I am checked every 6 months - she even took photos of my retinas they were so perfect! ~debbie y

As was sorting through the genes transcribed by the VDR I noticed that several of them were involved with retinal structure. I suspect the improvements in your eyes are not just due to reduced inflammation, but also increased transcription of these retinal structure proteins. ..Trevor..

Adequate eye protection is essential

See Protecting Your Eyes

-I started wearing my Bolle 100s around the house, and stayed inside until I get my 2% NoIRsSpecial sunglasses worn by Marshall Protocol patients to block light. 207s. WOW - just by wearing the Bolle's inside, the spots in my eyes went down about 80% in about 8hrs! After 4-5 days of wearing Bolle's inside, I'd say my spots are about 10%-20% of what they were (yay!). I just recv'd my 207s so now I can go outside. btw, Trevor said it was essential that I wear Bolle's inside and 2%'s outside, especially because of my retinopathy. ~rc45guy

Numerous anecdotal reports confirm the effects of increased and decreased light on the eyes of patients with Th1 inflammation.

See also:

Eye Inflammation

Eye inflammation, vision, and bacteria

Testimonials to the need to wear adequate eye protection.

Larsen, N., F. K. Vogensen, et al. (2010). “Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults.” PLoS One 5(2): e9085. 20140211

BACKGROUND: Recent evidence suggests that there is a link between metabolic diseases and bacterial populations in the gut. The aim of this study was to assess the differences between the composition of the intestinal microbiota in humans with type 2 diabetes and non-diabetic persons as control. METHODS AND FINDINGS: The study included 36 male adults with a broad range of age and body-mass indices (BMIs), among which 18 subjects were diagnosed with diabetes type 2. The fecal bacterial composition was investigated by real-time quantitative PCR (qPCR) and in a subgroup of subjects (N = 20) by tag-encoded amplicon pyrosequencing of the V4 region of the 16S rRNA gene. The proportions of phylum Firmicutes and class Clostridia were significantly reduced in the diabetic group compared to the control group (P = 0.03). Furthermore, the ratios of Bacteroidetes to Firmicutes as well as the ratios of Bacteroides-Prevotella group to C. coccoides-E. rectale group correlated positively and significantly with plasma glucose concentration (P = 0.04) but not with BMIs. Similarly, class Betaproteobacteria was highly enriched in diabetic compared to non-diabetic persons (P = 0.02) and positively correlated with plasma glucose (P = 0.04). CONCLUSIONS: The results of this study indicate that type 2 diabetes in humans is associated with compositional changes in intestinal microbiota. The level of glucose tolerance should be considered when linking microbiota with metabolic diseases such as obesity and developing strategies to control metabolic diseases by modifying the gut microbiota.

Selective vitamin D receptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61032-X/abstract

Patient interviews

Chris Eastlund

diabetes, sarcoidosis, irritable bowel syndrome

Read the interview


Interviews of patients with other diseases are also available.

Patients experiences

My blood sugar is back to normal readings, now, too with my latest A1C at 5.2 with no Metformin! I will document that change in my profile…I'm thrilled with my progress! With graditude, Sue

Sue Lyons, MarshallProtocol.com

Dear MPKB Reader: You have arrived at one of the articles that has not yet completed the development and review process in the knowledge base. Some of the content here may be helpful, but please know that this page is not complete. There are about 400 articles in the KB, and this is one we are still working on. Thanks for your patience.

Notes and comments

<DiseaseHierarchy>

  • Legacy content

http://www.lipidsonline.org/news/article.cfm?aid=9682

Conversely, harmful bacteria may deregulate genes mediating energy metabolism, and can produce toxins that mutate DNA, affecting the nervous and immune systems. The outcome is various forms of chronic disease, including obesity, diabetes and even cancers.22) 23) 24)

Liping Zhao

Diabetes. 2007 Jul;56(7):1761-72. Epub 2007 Apr 24. Metabolic endotoxemia initiates obesity and insulin resistance.25)

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Institute of Molecular Medicine, I2MR Toulouse, France. Comment in: Diabetes. 2007 Dec;56(12):e20; author reply e21. J Hepatol. 2008 Jun;48(6):1032-4. Abstract Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases. PMID: 17456850

From: Sue Lyons Date: 2011-03-24 20:44:55 Reply: http://www.marshallprotocol.com/reply.php?topic_id=7078

Janet, your suggestions to watch my blood sugar closely was timely as the day you wrote to me, I had a very low blood sugar episode while exercising! I immediately stopped all diabetes meds and exercising until my blood sugar became more stable! Thank you for the advise!

I am now off off meds (except Benicar and Mino.) I am exercising and maintaining my blood sugar and energy levels well! I feel wonderful! I had an appointment with my Pulmonologist today and he was thrilled with my progress! (He really is amazed as much as anything as he didn't think I would live longer than 2005!)

My sincere appreciation to Dr. Marshall, his team, and all MP supporters for giving me my life back!!! Sue

N Engl J Med. 2011 Mar 10;364(10):907-17.Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G; ROADMAP Trial Investigators.

Collaborators (294) Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. haller.hermann@mh-hannover.de Abstract BACKGROUND: Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria.

METHODS: In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points.

RESULTS: The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events–81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)–but a greater number had fatal cardiovascular events–15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P=0.02).

CONCLUSIONS: Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.).

PMID: 21388309 [

N Engl J Med. 2011 Mar 10;364(10):970-1.Preemptive olmesartan for the delay or prevention of microalbuminuria in diabetes. Ingelfinger JR.

PMID: 21388316

ORIALPreemptive Olmesartan for the Delay or Prevention of Microalbuminuria in Diabetes Julie R. Ingelfinger, M.D. N Engl J Med 2011; 364:970-971March 10, 2011 ArticleReferences Patients with either type 1 or type 2 diabetes mellitus are at high risk for chronic kidney disease, which is usually first evident with the onset of microalbuminuria. There is overall consensus that agents that block the renin–angiotensin system — particularly angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) — slow the progression of chronic kidney disease in patients with diabetes who already have microalbuminuria. Long-term trials with losartan (the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] trial)1 and irbesartan2 showed that ARBs slowed the course of diabetic nephropathy in patients with baseline evidence of renal involvement. Many other trials have shown that ACE inhibitors alone or with other agents, including ARBs, decrease microalbuminuria. The concept of preemptive renoprotective therapy has gained traction, since diabetic nephropathy constitutes a major cause of end-stage renal disease worldwide. For example, in a small study involving 43 patients with type 2 diabetes, Ikeda et al. observed that when olmesartan (at a dose of 20 mg) was substituted for other ARBs, there was a further decrease in microalbuminuria.3 In yet another small study of ARBs,4 telmisartan appeared to be more potent than other ARBs, including olmesartan, perhaps through its effects on microalbuminuria but also through its effects on markers of tubulointerstitial damage. This issue of the Journal contains the primary results of the Randomized Olmesartan and Diabetes Microalbuminuria Prevention trial (ROADMAP; ClinicalTrials.gov number, NCT00185159),5 a multicenter, multinational trial, in which nearly 4500 patients with type 2 diabetes without microalbuminuria were randomly assigned to receive 40 mg of olmesartan, an angiotensin-receptor antagonist, once daily, or placebo and were followed for a median of 3.2 years. The study aimed to determine whether early therapy with olmesartan in patients with type 2 diabetes mellitus would avert or forestall the onset of microalbuminuria. Control of blood pressure was excellent in both study groups, since all patients, irrespective of study group, were treated with agents other than blockers of the renin–angiotensin system to achieve a target blood pressure. Olmesartan was, as anticipated, associated with increased time to the onset of microalbuminuria. The primary outcome was the time to the onset of microalbuminuria, not the degree of microalbuminuria. There was no significant difference in renal function between the two study groups (a doubling of the serum creatinine level occurred in approximately 1% of the patients in each study group). Although the analysis is markedly underpowered for cardiovascular end points, given the very small number of events in a relatively healthy population of persons with type 2 diabetes, the cardiovascular results of this trial have raised concerns, even before publication. Nonfatal cardiovascular events occurred in 81 patients in the olmesartan group (3.6%) and 91 in the control group (4.1%); however, fatal cardiovascular events occurred in more patients in the olmesartan group than in the placebo group — 15 (0.7%) as compared with 3 (0.1%) (P=0.01). This difference was attributable in part to a higher number of deaths from cardiovascular causes among patients with preexisting coronary heart disease. The fact that these signals go in opposite directions, together with the feeling that the study was underpowered to determine cardiovascular risk, has led many to comment that these results may well be due to chance. However, this possible cardiovascular safety signal, together with a similar signal from the Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT, NCT00141453),6 has led to an ongoing investigation by the Food and Drug Administration (FDA). In ORIENT, 566 patients with type 2 diabetes, who differed from the patients in the ROADMAP trial in that they had overt nephropathy, were randomly assigned to olmesartan (at a dose of 10 to 40 mg daily) or to placebo. Additional antihypertensive medications were permitted, including ACE inhibitors but not including ARBs. The end point was a composite of the time to the first event of doubling of the serum creatinine level, end-stage renal disease, or death from any cause. In ORIENT, there were 10 deaths in the olmesartan group and 3 in the control group. Other ARBs — losartan, valsartan, irbesartan, and candesartan cilexetil — have not been associated with a signal of increased cardiovascular mortality. Is there anything different about olmesartan? The drug has been promoted as a medication that helps patients reach blood-pressure goals rapidly.7 The dose used in the current study, 40 mg per day, was higher than that used in many other studies. Was the increase in cardiovascular mortality due to a blood pressure that was too low in patients at high risk? Indeed, in the ROADMAP trial, the excess cardiovascular deaths occurred mainly among patients in the lowest quartile of blood pressure. In other studies involving other agents, cardiovascular mortality was higher among patients with coronary artery disease in whom the systolic blood pressure was below 120 mm Hg.8,9 The FDA has not yet announced any conclusions concerning the risk of death with olmesartan. In fact, their Web site10 states, “the [FDA] has not concluded that [olmesartan] increases the risk of death” and goes on to say that the agency “believes that the benefits of [olmesartan] in patients with high blood pressure continue to outweigh its potential risks.” Many clinicians and investigators have expressed the opinion that olmesartan does not actually increase risk, pointing to the lack of power in the analysis and the many published studies with ARBs in which no cardiovascular risk signal appeared and to the fact that olmesartan was approved in 2002, rendering it likely that danger signals would have been evident by now. Should the question of increases in fatal cardiovascular events in ROADMAP change our approach to renoprotective therapy? Most nephrologists and cardiologists have argued that the benefits of olmesartan outweigh the very small risks, particularly since the FDA specifically has not issued a black-box warning nearly 8 months after the investigation was launched. Others would argue that there are many ACE inhibitors and ARBs that have not been associated with a signal of increased cardiovascular death, so why not prescribe one of those agents? ROADMAP is a very large study involving patients with diabetes who did not have evidence of renal disease at baseline, and the primary results indicate that preemptive therapy with an ARB may well delay or prevent the onset of microalbuminuria — findings that are important, albeit anticipated. These results provide hope that it may be possible to prevent progressive chronic kidney disease in the many persons worldwide who have type 2 diabetes mellitus.

Effects of Olmesartan Medoxomil, an Angiotensin II Type 1 Receptor Antagonist, on Plasma Concentration of B-Type Natriuretic Peptide, in Hypertensive Patients with Type 2 Diabetes Mellitus: A Preliminary, Observational, Open-Label Study. http://www.ncbi.nlm.nih.gov/pubmed/21184621

Angiotensin II type 1 (AT(1)) receptor antagonists (angiotensin receptor blockers [ARBs]) are widely used for the treatment of not only hypertension but also cardiac dysfunction. B-type natriuretic peptide (BNP) is secreted mainly by the cardiac ventricle and plays an important role in the regulation of blood pressure (BP) and body fluid. It has been established that the plasma level of BNP is increased in patients with chronic heart failure in proportion to the severity of cardiac dysfunction. Because cardiac dysfunction is closely associated with a high risk of mortality in patients with diabetes mellitus, early identification and prevention of cardiac dysfunction are important. The objective of this study was to determine the effects of olmesartan medoxomil, a novel ARB, on the plasma level of BNP in hypertensive patients with type 2 diabetes. Methods: This was a preliminary, prospective, observational, open-label study. Sixty-eight type 2 diabetic patients with hypertension (systolic BP [SBP] 140 mmHg or diastolic BP [DBP] 90 mmHg) received olmesartan medoxomil 10-20 mg/day for 24 weeks. Plasma levels of BNP, as well as several clinical parameters of glycaemic control and lipid metabolism, were compared before and after 24 weeks of treatment. Another group consisting of 22 age- and body mass index-matched subjects not treated with olmesartan medoxomil was observed for reference purposes. Results: In the olmesartan medoxomil group, mean ± SD SBP decreased from 152.8 ± 16.4 at baseline to 146.8 ± 14.4 mmHg after 24 weeks' treatment (p < 0.05); similarly, mean ± SD DBP decreased from 85.6 ± 10.5 to 81.3 ± 11.6 mmHg (p < 0.05). In 53 subjects in whom plasma levels of BNP could be measured both before and after treatment, mean ± SD BNP decreased from 41.3 ± 49.9 to 32.5 ± 36.3 pg/mL (p < 0.05). Change in plasma BNP level over the 24-week treatment period in the olmesartan medoxomil group was not correlated with change in SBP or DBP. Multiple regression analysis revealed that change in plasma BNP level was not correlated with baseline value of or change in any other parameters. No other parameters in the olmesartan medoxomil group, and no parameters in the non-olmesartan medoxomil reference group, showed significant changes. Conclusion: The current preliminary study showed that olmesartan medoxomil treatment might decrease plasma BNP levels, independent of its BP-lowering effect, in hypertensive patients with type 2 diabetes.

Type 2 diabetes as an inflammatory diseaseMarc Y. Donath1 & Steven E. Shoelson2 About the authors

topof page Abstract

Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.

Olmesartan ameliorates peripheral nerve dysfunction in Zucker diabetic fatty rats. Sugimoto K, Kojima K, Baba M, Yasujima M. Source

aDepartment of Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan bDepartment of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan.

Abstract

OBJECTIVE:

Angiotensin (ANG) II type 1 receptor (AT1R) blockers have neuroprotective effects against neuronal lesions. The present study examines whether the AT1R blocker olmesartan improves peripheral nerve dysfunction in rats with type 2 diabetes.

METHODS:

Fourteen-week-old male type 2 diabetic Zucker diabetic fatty (ZDF) rats were orally administered with olmesartan (6 mg/kg per day; n = 7) or not treated (n = 7) and then followed up for nine weeks. Age-matched and sex-matched nondiabetic lean rats served as controls (n = 7).

RESULTS:

Olmesartan for 9 weeks did not influence blood glucose and A1c levels that were higher in untreated ZDF (U-ZDF) rats than in control rats. In U-ZDF rats, myelinated fiber density and myelin areas of myelinated fibers in peroneal nerves significantly increased and decreased, respectively, and the intraepidermal nerve fiber density (IENFD) of footpad skin tended to decrease. The U-ZDF rats developed mechanical hyperalgesia, thermal hypoalgesia and slower sensory and motor nerve conduction in the sciatic-tibial nerves. Olmesartan increased myelin areas and IENFD and ameliorated sensory nerve conduction deficits. These beneficial effects of olmesartan were associated with ANG II and insulin receptor upregulation in sensory neurons as well as deactivation of Erk1/2 in sciatic nerves.

CONCLUSION:

Olmesartan appears to improve the structure and function of small and large nerves and upregulate ANG II and insulin receptors in sensory neurons of rats with type 2 diabetes.

PMID: 21602711 [PubMed - in process]

<IncompleteNotice>

====== Test: Glucose ======

should this be under symptoms, under diabetes (I or II)???

If most of the morbidity in patients with diabetes is caused by high blood glucose levels, then control of those levels should return the system to normal and the patient's health problems should disappear. However, in one recent study this strategy of more intensive glucose control resulted in increased risk of death.1

1. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.

H.H. Weng26)

HgA1c is a long-term measure of blood-sugar control. It is useful because it measures the average control over a long period of time. I would not be surprised if it elevated mildly, due to herx,while the pathogens were being killed.

Remember that an untreated diabetic would expect a gradual increase in hgA1c as their condition worsened over their lifetime. At some point, however, you should expect yours to start dropping, but probably not until most of the herx is behind you.

..Trevor..

The Hemoglobin A1C test is not directly related to the CBC hemoglobin. It is used to get an idea of what your blood sugars have been over the last two to three months.

There is some information on it here… Hemoglobin A1C

When your fasting blood sugar has “jumped” on a lab test, your Dr may order the Hemoglobin A1C to check if there is any reason to run further tests.

You should request the Hemoglobin A1C test before going through a glucose tolerance test which requires multiple blood samples.

find more about Barney's blood glucose - very high - http://www.bbc.co.uk/blogs/today/tomfeilden/2008/10/drugs_on_test.html

Low Blood Sugar (Hypoglycemia)

Low blood sugar can make you feel: -shaky -weak -confused -irritable -hungry -tired -you may sweat a lot -you may get a headache

If you have these symptoms, check your blood sugar.

If it is 70 or lower, have one of the following right away:

· 3 or 4 glucose tablets · 1 serving of glucose gel (check the label—you’ll want the amount equal to 15 grams of carbohydrate) · 1/2 cup (4 ounces) of any fruit juice · 1/2 cup of a regular (not diet) soft drink · 1 cup (8 ounces) of milk · 5 or 6 pieces of hard candy (jelly beans are convenient to carry with you) · 1 tablespoon of sugar or honey

After 15 minutes, check your blood sugar again.

If it is still too low, have another serving.

Repeat until your blood sugar level is 70 or higher.

If it will be an hour or more before your next meal, have a snack.

Glucose test is described here.

Blood glucose meters

Consumer Reports revealed the results of their latest testing in the Sept. 08 issue. Here is what they found:

-Only one blood glucose meter, the OneTouch UltraMini, was rated excellent overall. It has top accuracy and consistency scores and was very easy to use. $20 and test strips $1.14 each

-The Ascensia Contour blood glucose meter was rated a very good choice because of is excellent accuracy and combination of features, and its very good consistency. $80 and test strips $1.10 each

-The ReliOn Ultima, another very good choice, was also a CR Best Buy at just $9 and its testing strips cost just 44 cents each.

Gut microbiota and diabetes: from pathogenesis to therapeutic perspective

Authors: Burcelin, R; Serino, M; Chabo, C; Blasco-Baque, V; Amar, J

Author Full Names: Burcelin, Remy; Serino, Matteo; Chabo, Chantal; Blasco-Baque, Vincent; Amar, Jacques

Source: ACTA DIABETOLOGICA, 48 (4):257-273; 10.1007/s00592-011-0333-6 DEC 2011

Language: English

Document Type: Review

Author Keywords: Gut microbiota dysbiosis; Prebiotic and probiotic; Inflammation; Type 2 diabetes; Obesity; High throughput sequencing

KeyWords Plus: HIGH-FAT DIET; HUMAN INTESTINAL MICROBIOTA; CORONARY-ARTERY-DISEASE; LOW-DENSITY-LIPOPROTEIN; GLUCAGON-LIKE PEPTIDE-1; INULIN-TYPE FRUCTANS; 16S RIBOSOMAL-RNA; GERM-FREE MICE; INSULIN-RESISTANCE; METABOLIC SYNDROME

Abstract: More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10-20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as t! he low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain.

These gains are already becoming apparent. At the Paris conference, Jens Nielsen, a systems biologist at Chalmers University of Technology in Gothenburg, Sweden, showed that the gut’s microbial genes may be a better predictor of type 2 diabetes than established risk factors such as waist–hip ratio or body mass index. Other researchers presented results from MetaHIT that suggest that gut bacteria are more accurate markers for leanness or obesity than any of our own genetic variants.

References

1)
The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus.
Westman EC, Yancy WS Jr, Mavropoulos JC, Marquart M, McDuffie JR
Nutr Metab (Lond)5p36(2008 Dec 19)
2)
Effects of a low-carbohydrate diet on glycemic control in outpatients with severe type 2 diabetes.
Haimoto H, Sasakabe T, Wakai K, Umegaki H
Nutr Metab (Lond)6p21(2009 May 6)
3)
Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal.
Accurso A, Bernstein RK, Dahlqvist A, Draznin B, Feinman RD, Fine EJ, Gleed A, Jacobs DB, Larson G, Lustig RH, Manninen AH, McFarlane SI, Morrison K, Nielsen JV, Ravnskov U, Roth KS, Silvestre R, Sowers JR, Sundberg R, Volek JS, Westman EC, Wood RJ, Wortman J, Vernon MC
Nutr Metab (Lond)5p9(2008 Apr 8)
4)
Optimizing the therapeutic benefits of exercise in Type 2 diabetes.
Praet SF, van Loon LJ
J Appl Physiol103p1113-20(2007 Oct)
5)
Prevention of microalbuminuria in patients with type 2 diabetes and hypertension.
Menne J, Izzo JL Jr, Ito S, Januszewicz A, Katayama S, Chatzykirkou C, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G, Haller H
J Hypertens30p811-8; discussion 818(2012 Apr)
6)
Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes.
Raff U, Ott C, Ruilope LM, Menne J, Haller H, Schmieder RE
J Hypertens32p2267-76; discussion 2276(2014 Nov)
7)
Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes.
Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S
Am J Physiol Endocrinol Metab292pE740-7(2007 Mar)
9)
Interleukin-6 induces cellular insulin resistance in hepatocytes.
Senn JJ, Klover PJ, Nowak IA, Mooney RA
Diabetes51p3391-9(2002 Dec)
10)
Macrophage-secreted factors induce adipocyte inflammation and insulin resistance.
Permana PA, Menge C, Reaven PD
Biochem Biophys Res Commun341p507-14(2006 Mar 10)
11)
Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice.
Ilan Y, Maron R, Tukpah AM, Maioli TU, Murugaiyan G, Yang K, Wu HY, Weiner HL
Proc Natl Acad Sci U S A107p9765-70(2010 May 25)
12)
Clinical outcome of single versus sequential grafts in coronary bypass operations at ten years' follow-up.
Meeter K, Veldkamp R, Tijssen JG, van Herwerden LL, Bos E
J Thorac Cardiovasc Surg101p1076-81(1991 Jun)
13)
A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats.
Lu M, Patsouris D, Li P, Flores-Riveros J, Frincke JM, Watkins S, Schenk S, Olefsky JM
Am J Physiol Endocrinol Metab298pE1036-48(2010 May)
14)
Dietary blueberry attenuates whole-body insulin resistance in high fat-fed mice by reducing adipocyte death and its inflammatory sequelae.
DeFuria J, Bennett G, Strissel KJ, Perfield JW 2nd, Milbury PE, Greenberg AS, Obin MS
J Nutr139p1510-6(2009 Aug)
15)
Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance.
Mauer J, Chaurasia B, Plum L, Quast T, Hampel B, Blüher M, Kolanus W, Kahn CR, Brüning JC
PLoS Genet6pe1000938(2010 May 6)
16)
The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide.
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD
PLoS One5pe9505(2010 Mar 3)
17)
Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes.
Miklossy J, Qing H, Radenovic A, Kis A, Vileno B, Làszló F, Miller L, Martins RN, Waeber G, Mooser V, Bosman F, Khalili K, Darbinian N, McGeer PL
Neurobiol Aging31p1503-15(2010 Sep)
19)
The effect of oxytetracycline on insulin resistance in obese mice.
Bégin-Heck N, Bourassa M, Heick HM
Biochem J142p465-75(1974 Sep)
20)
Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults.
Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, Al-Soud WA, Sørensen SJ, Hansen LH, Jakobsen M
PLoS One5pe9085(2010 Feb 5)
22)
Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.
Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI
Proc Natl Acad Sci U S A104p979-84(2007 Jan 16)
23) , 24) , 25)
Metabolic endotoxemia initiates obesity and insulin resistance.
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R
Diabetes56p1761-72(2007 Jul)
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