Hypertension and Diabetes

Relationships and Management

By

Roberto Victor Illa, M.D.

A Higher Estimated Incidence

Clinical Diabetes 23:51-52, 2005© American Diabetes Association ®, Inc., 2005 Editorial

The Diabetes Pandemic: Looking for the Silver Lining

K.M. Venkat Narayan, MD, MPH, FRCP, FACP

Diabetes is an American epidemic. One in three Americans born in 2000 is projected to develop diabetes. Diabetes is a pandemic. In 2003, 194 million people worldwide, ranging in age from 20 to 79 years, had diabetes. By 2025, this number is projected to increase by 72% to 333 million, and nearly 80% of these cases will be in the poorer industrializing countries.

……about 85% of newly-diagnosed patients have no family history of the disease.

Type 1 Diabetes: new perspectives on disease pathogenesis and treatment.

Atkinson A, Esienbarth GS. Lancet 2001: 358:221-29

The Frequency with which Hypertension and Diabetes Occur Together

“The JNC report recommends a blood pressure goal of < 140/90 mm for individuals with uncomplicated hypertension. However, hypertensive patients with diabetes and/or chronic kidney disease require a lower blood pressure goal.

Patients with diabetes have a substantially higher incidence of hypertension, and patients with hypertension have 2.5-fold greater risk of developing diabetes within 5 yrs. (N Engl J Med 2000:342:905-912. Gress TW et al.).

Moreover, the coexistence of these conditions is especially deleterious because of their irrefutable connection to all CV disease, stroke, progression of renal disease and diabetic retinopathy (Hypertension 2003:42:1206-1252. Chobanian AV et al).

Diabetes Care. 2005 Nov;28(11):2756-61.Related Articles, Links

Increased mortality risks of pre-diabetes (impaired fasting glucose) in Taiwan.

Wen CP, Cheng TY, Tsai SP, Hsu HL, Wang SL.

Division of Health Policy Research, National Health Research Institutes, Taiwan, ROC. cwengood@nhri.org.tw

36,386 subjects over 11 years. Ages 40-69 IFG = 110-125 mg% >75% colledge graduates. White-collar civil servants and teachers.

A Unifying Theory

To Explain the Link Between

Diabetes Mellitus and Hypertension

The Conventional ExplanationExplains Nothing!

It

Does not Elucidate or attempt to explain

the relationship

between

Diabetes of Various Etiologies

(e.g. Drug induced and Epidemic)

or the higher frequency of

Diabetes in Hypertensives.

The Source of “Insulin Resistance” must emanate, at least, in part, from a CNS lesion.

Beta blocker and diuretic therapy increase risk of developing diabetes

Williams B, Poulter NR, Brown MJ, etal. Guidelines for management of hypertension; report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004: 18:139-85.

Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002: 359: 995-1003.

Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004: 363: 2022-31.

The Demise of The Metabolic Syndrome?From Medscape Diabetes & Endocrinology

Expert CommentaryThe Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth -- Where Does the International Diabetes Federation Stand? Posted 10/11/2005

Paul Z. Zimmet, MD; George Alberti, MA, DPhil, BMBCh Setting the Scene: The American Diabetes Association/European Association for the Study of Diabetes Shot Across the Bow of the Metabolic Syndrome

Although the underlying cause of the metabolic syndrome remains controversial, the ultimate importance of the syndrome is that it helps identify individuals at high risk for cardiovascular disease (CVD) and type 2 diabetes.[1] This is clearly a major benefit of its widespread recognition and acceptance. Nevertheless, a recent position paper jointly sponsored by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)[2,3] has questioned the existence and utility of the metabolic syndrome. Kahn and colleagues,[2,3] on behalf of these organizations, have suggested that the time has come for a critical appraisal of the metabolic syndrome. They claim that there is confusion about the syndrome. If this is so, then they have further added to this confusion with a long and tortuous exposé of its supposed problems. Their article, we believe, indicates a number of misconceptions and inconsistencies that we would like to address. Many of the issues that they raise have been covered in the recent International Diabetes Federation (IDF) Consensus,[4] which they barely quote.

We recognize the importance of debate; however, the appearance of this initiative on behalf of 2 of the world's leading regional diabetes organizations raises questions of motive and timing. Are the criticisms part of a "turf protection" scenario[5] or do they have a valid scientific basis?

In recent years, there has been increasing interest in the metabolic syndrome by the American Heart Association, the American College of Cardiology, the International Atherosclerosis Society, and other specialist groups in diabetes, insulin resistance, hypertension, and cardiology worldwide, effectively removing it from the province of pure diabetes. Thus, far from the metabolic syndrome being an offshoot of type 2 diabetes, one could consider that type 2 diabetes is but one of several manifestations of the metabolic syndrome.[1]

The ADA/EASD position paper[2,3] was released in a burst of publicity, and the issue received considerable media exposure. The authors of the ADA/EASD statement direct their main criticisms at earlier definitions, namely, those of the World Health Organization (WHO)[6] and the National Cholesterol Education Program Adult Treatment Panel III (ATP III).[7] Some investigators in the diabetes field, after embracing the concept wholeheartedly for about 15 years, are having "second thoughts" about the metabolic syndrome, not unreasonable in, providing that there are cogent arguments to do so. Several of the authors of the statement have been vigorous proponents of the metabolic syndrome. As recently as 2 years ago, Zachary Bloomgarden, MD,[8] reported on a presentation by Professor Ferrannini, one of the ADA/EASD paper authors, at the Endocrine Society's 85th Annual Meeting:

Indicators of the Metabolic Syndrome?

Hypertriglyceridemia is commonly seen in diabetes mellitus and has traditionally been associated with the “metabolic syndrome”. However, hypertriglyceridemia is also a marker for a variety of viral infections.

Adenovirus

CMV

HIV

Increased abdominal girth, or waist hip ratios, have also been

proclaimed to be an indication of “metabolic syndrome”. However, diabetes is common in third world nations where smaller abdominal girths and poor nutrition is common.

Hypertriglyceriedemia a marker for any severe viral infection. HIV.CMV.Adenovirus and Diabetes mellitus

Pediatr Hematol Oncol. 2003 Sep;20(6):445-51. IVIG treatment of adenovirus infection-associated

macrophage activation syndrome in a two-year-old boy: case report and review of the literature. Seidel MG, Kastner U, Minkov M, Gadner H. St. Anna Children's Hospital, Children Cancer Research Institute CCRI, Kinderspitalgasse 6, A-1090 Vienna, Austria. A 2-year-old boy with severe multiorgan disease (i.e., otitis, enteritis, bilateral pneumonia, encephalopathy, myocarditis, rash) was diagnosed with adenovirus-associated macrophage activation syndrome according to clinical and laboratory parameters (fever, hepatosplenomegaly, bicytopenia, hyperferritinemia, hypertriglyceridemia). He had no unusual history of earlier infections or a family history of hemophagocytic

syndrome or immune defects. Intravenous immunoglobulin was administered to prevent exacerbation of the suspected incipient hemophagocytic syndrome. Clarithromycin, a macrolide with immunomodulatory effect, was included in the antibiotic regimen of the progressive pneumonia, followed by rapid amelioration and remission of clinical and laboratory findings. Causal links between treatment and clinical improvement are discussed and a brief review of the recent literature is included.

CMV and Hypertriglyceridemia

Clin Microbiol Infect. 2004 May;10(5):468-70.

Cytomegalovirus mononucleosis as a cause of prolonged fever and prominent weight loss in immunocompetent adults.Rodriguez-Bano J, Muniain MA, Borobio MV, Corral JL, Ramirez E, Perea EJ, Perez-Cano R.Seccion de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Virgen Macarena, Sevilla, Spain. jrb@nacom.esFour immunocompetent adults presented with protracted fever lasting > 6 weeks and severe weight loss, associated with primary cytomegalovirus (CMV) infection. Each patient had spleen enlargement, lymphocytosis and hypertriglyceridaemia, but recovered spontaneously. A further 20 immunocompetent patients with primary CMV infection were also reviewed, and all presented the usual clinical picture of CMV mononucleosis. It was concluded that CMV mononucleosis should be considered in the differential diagnosis in patients with prolonged fever and weight loss if lymphocytosis is present.

Hypertriglyceridemia and HIV

Am J Med. 1989 Jan;86(1):27-31. Hypertriglyceridemia in the acquired immunodeficiency syndrome.Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierson RN.Metabolism Section, Veterans Administration Medical Center, San Francisco, California 94121.PURPOSE: A relationship between the induction of hypertriglyceridemia by cytokines and the cachexia seen in chronic infection has been proposed by other investigators. Since patients with the acquired immunodeficiency syndrome (AIDS) often experience progressive tissue wasting, we decided to examine serum lipid levels and body cell mass in patients with AIDS. PATIENTS AND METHODS: Serum lipid levels and body cell mass were measured in 32 patients with the acquired immunodeficiency syndrome (AIDS), eight asymptomatic subjects who were anti-human immunodeficiency virus (HIV) antibody positive, and 17 heterosexual and homosexual control subjects who did not have antibodies to HIV. RESULTS: Mean triglyceride concentrations and the prevalence of hypertriglyceridemia (50 percent) were significantly increased in patients with AIDS compared with control subjects (p less than 0.002 and p less than 0.005, respectively), whereas the mean triglyceride levels of HIV-positive subjects were intermediate. There were no differences in cholesterol levels among the three groups. Using total body potassium adjusted for height and age (KHT) as a measure of body cell mass, 16 of 32 patients with AIDS but none of the HIV-positive or control subjects had significant depletion of body cell mass. There was no direct relationship between triglyceride levels and KHT among AIDS or HIV-positive subjects. In patients with AIDS, mean triglyceride levels and the prevalence of hypertriglyceridemia were similar in the presence and absence of wasting. CONCLUSION: Hypertriglyceridemia is a common finding in AIDS and is independent of the degree of wasting.

Enterovirus and type I diabetes

AbstractThe development of type 1 diabetes mellitus (T1DM) has been linked to

exposure to environmental triggers, with Enteroviruses (EV) historically considered the prime suspects. Early serological studies suggested a link between EV infections and the development of T1DM and, though controversial, have been bolstered by more recent studies using more sensitive techniques such as direct detection of the EV genome by RT-PCR in peripheral blood. In this review, we consider the weight of evidence that EV can be considered a candidate trigger of T1DM, using three major criteria: (1) is EV infection associated with clinical T1DM, (2) can EV trigger the development of autoimmunity and (3) what would explain the putative association?

Department of Immunology, Guy's, King's and St Thomas' School of Medicine, London, United Kingdom

*Correspondence to Mark Peakman, Department of Immunology, Guy's, King's and St Thomas' School of Medicine, Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, UK.

Varela-Calvino R, Peakman M. Enterovirus and type I diabetes. Diabetes/Metabolism Research and reviews 2003. 19(6): 431-441

In a few years ¾ of all diabetes will be in the (malnourished) third world (Asia, India & Africa)

“The risk factors for the increasing prevalence among Asian Indians included high racial susceptibility, central obesity and insulin resistance even with a low Body Mass Index. "There are a number of people dying of diabetes, as insulin is either not available or unaffordable." Following a healthy lifestyle, exercising and following precautions were extremely important to prevent the onset of the disease. “Clin Nutr. 2005 Dec;24(6):1056-64. Epub 2005 Sep 26.  Effects of acute starvation on insulin resistance in obese patients with and without type 2 diabetes mellitus.Duska F, Andel M, Kubena A, Macdonald IA.Department of Internal Medicine II, The 3rd Faculty of Medicine, Srobarova 50, Kralovske Vinohrady University Hospital, Charles University, Prague, Czech Republic. fduska@yahoo.com

BACKGROUND & AIMS: Starvation decreases insulin sensitivity and glucose tolerance in both lean and obese (OB) non-diabetic subjects. Influence of drastic calorie reduction on insulin resistance in patient with type 2 diabetes (T2DM) is not known. METHODS: We enrolled 10 T2DM (diabetes duration 11.1+/-7.9 years) and 10 OB age and weight-matched subjects and performed isoglycaemic hyperinsulinaemic clamp (two 120 min phases of 60 and 120 mIU min-1 m-2 i.v. insulin) with indirect calorimetry at baseline and after 60 h of fasting. RESULTS: After starvation insulin-mediated glucose disposal decreased significantly in both hyperinsulinaemic phases in T2DM (phase 1: from 46+/-28 to 33+/-17, P<0.04; phase 2 from 122+/-47 to 80+/-30 microg kg-1 min-1, P<0.01) as well as in OB (phase 1: from 94+/-52 to 52+/-24, P<0.04; phase 2: from 131+/-46 to 106+/-43 microg kg-1 min, P<0.01). Both oxidative and non-oxidative components of glucose disposal tended to be reduced after fasting. A change of insulin sensitivity was found to be highly dependent upon pre-starvation conditions: more insulin resistant subjects tended to maintain (or modestly improve) insulin resistance whilst subjects with better insulin sensitivity tended to worse it. CONCLUSION: Insulin sensitivity worsens similarly in both T2DM and OB subjects during 60-h fast. The change is probably predictable according to pre-starvation insulin sensitivity.

Thin Cambodians have high incidence of diabetesThe Lancet 2005; 366:1633-1639 DOI:10.1016/S0140-6736(05)67662-3 Diabetes and associated

disorders in Cambodia: two epidemiological surveys Hilary King a, Lim Keuky b, Serey Seng b, Touch Khun b, Gojka Roglic c and Michel Pinget a

Summary Background The Asia-Pacific region is thought to be severely affected by diabetes. However, reliable, standardised data on prevalence and characteristics of glucose intolerance in Asian populations remain sparse. We describe the results of two field surveys undertaken in Cambodia in 2004. Methods 2246 randomly selected adults aged 25 years and older were examined in two communities, one rural (Siemreap) and one semi-urban (Kampong Cham). The diagnosis of diabetes and impaired glucose tolerance was based on 2-h blood glucose estimation using criteria recommended by the latest report of a WHO Expert Group. Blood pressure, anthropometry, habitual diet, and other relevant characteristics were also recorded. Findings Prevalence of diabetes was 5% in Siemreap and 11% in Kampong Cham. Prevalence of impaired glucose tolerance was 10% in Siemreap and 15% in Kampong Cham. About two-thirds of all cases of diabetes were undiagnosed before the survey. Prevalence of hypertension was 12% at Siemreap and 25% at Kampong Cham.

Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies

The Lancet 2006; 368:666-678Abel Romero-Corral MD  Victor M Montori MD   Prof Virend K Somers MD  Josef Korinek MD   Randal J Thomas MD,   Thomas G Allison PhD   Farouk Mookadam MD   and   Francisco Lopez-Jimenez MD SummaryBackground Studies of the association between obesity, and total mortality and cardiovascular events in patients with coronary artery disease (CAD) have shown contradictory results. We undertook a systematic review to determine the extent and nature of this association.Methods We selected cohort studies that provided risk estimates for total mortality, with or without cardiovascular events, on the basis of bodyweight or obesity measures in patients with CAD, and with at least 6 months' follow-up. CAD was defined as history of percutaneous coronary intervention, coronary artery bypass graft, or myocardial infarction. We obtained risk estimates for five predetermined bodyweight groups: low, normal weight (reference), overweight, obese, and severely obese.Findings We found 40 studies with 250,152 patients that had a mean follow-up of 3·8 years. Patients with a low body-mass index (BMI) (ie, <20) had an increased relative risk (RR) for total mortality (RR=1·37 [95% CI 1·32–1·43), and cardiovascular mortality (1·45 [1·16–1·81]), overweight (BMI 25–29.9) had the lowest risk for total mortality (0·87 [0·81–0·94]) and cardiovascular mortality (0·88 [0·75–1·02]) compared with those for people with a normal BMI. Obese patients (BMI 30–35) had no increased risk for total mortality (0·93 [0·85–1·03]) or cardiovascular mortality (0·97 [0·82–1·15]). Patients with severe obesity (≥35) did not have increased total mortality (1·10 [0·87–1·41]) but they had the highest risk for cardiovascular mortality (1·88 [1·05–3·34]).Interpretation The better outcomes for cardiovascular and total mortality seen in the overweight and mildly obese groups could not be explained by adjustment for confounding factors. These findings could be explained by the lack of discriminatory power of BMI to differentiate between body fat and lean mass.

Coxsackie B4 virus and hyperglycemia

J Med Virol 1992-10-1 38(2) 124-31Coxsackievirus B4 infection alters thymic, splenic, and peripheral lymphocyte repertoire preceding onset of hyperglycemia in mice. Chatterjee NK, Hou J, Dockstader P, Charbonneau T, Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509. Diabetogenic Coxsackievirus B4 infection may trigger autoimmune islet loss in diabetes-susceptible mice, resulting in hyperglycemia in nearly 90% of the animals at 6-8 weeks postinfection (p.i.). To ascertain whether changes in lymphocyte repertoire following infection could predispose these animals to diabetes, alterations in their thymic, splenic, and peripheral lymphocytes were analyzed. Additionally, lymphocyte changes were correlated with the virus load in these tissues and with lymphocyte migration to the inflammatory pancreas.

Coxsackie B4 virus and hyperglycemiaSplenic B lymphocytes more than doubled at 72 hr p.i. and then continuously decreased by 16% of the noninfected controls at 8 weeks p.i. T lymphocytes (CD4+ + CD8+) decreased by about 50% at 72 hr and then increased to the control level by 8 weeks p.i.; CD8+ subset continuously decreased by 40% of the control at 8 weeks, resulting in a 67% increase in CD4+/CD8+ ratio. Macrophages and CD5+ B subset increased at 72 hr and then dipped by 93% and 84%, respectively, at 8 weeks. In contrast, peripheral B lymphocytes increased by 74% and T lymphocytes decreased by 11% at 8 weeks p.i. Macrophages increased by twofold at 72 hr and then dipped slightly (6%) at 8 weeks, whereas CD5+ B subset increased by 245%. Most prominent thymic T lymphocyte alteration was reflected by about 150% increase in CD4- CD8- cells at 8 weeks p.i. The peak viremia occurred at 72 hr p.i., with highest and lowest virus in the spleen and thymus, respectively. The thymus cleared virus by 3 days, the other tissues by 7 days. Insulitis and acinar necrosis followed infection; infiltrating lymphocytes were mostly CD4+. Virus-induced abnormal lymphocyte maturation may contribute to the development of insulitis and hyperglycemia.

Reconciling genetic and infectious etiologies of diabetes

The environmental inciting agent

Substrate of mammalian genetic susceptibility to diabetes mellitus

Highly susceptible Moderately susceptible Moderately resistant Highly resistant

Early viremia in DM?

Could the vascular endothelium also be a target of this putative virus?

This would be consistent with the increase in cardiovascular mortality which precedes

clinical diabetes and the higher incidence of diabetes among hypertensives.

ARB’s seem to rejuvenate the vascular endothelium

Could this be because they, to some extent, ameliorate the damage done to the

endothelium

by the viral infection?

This would fit the reduced incidence of new onset diabetes seen with Losartan and

Valsartan in the LIFE and VALUE studies (about 25%).

Viral infection of endothelium and liver

CRP binds to endothelium + upregulates AT1 receptors in vascular smooth muscle. Circulation 2003:107:1783

Inflammation of endothelium

Liver stimulated to produce CRP (Liver enzyme elevations very common in early DM. )

Increased intimal atherogenesis &

Increase in stimulation/formation of AT1 receptors

Hypertension

1. ARB’s block AT1 receptors and (?) formation of new AT1 receptors

2. or, generation of CRP by liver (?).

3. or,… do they block inflammation of liver by virus? (see Valmark Study)

Increase in IL6* and CRP

Increase in Angiotensin II

Braz J Med Biol Res. 2002 Sep;35(9):1001-15.

* J Physiol. 2006 Jul 6

Valsartan, Blood Pressure Reduction, and C-Reactive Protein

Hypertension. 2006;48:73.)© 2006 American Heart Association, Inc. Original Articles

Primary Report of the Val-MARC Trial

Paul M Ridker; Eleanor Danielson; Nader Rifai; Robert J. Glynn for the Val-MARC Investigators From the Center for Cardiovascular Disease Prevention, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Dr Paul Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail pridker@partners.org

Increased levels of high-sensitivity C-reactive protein (hsCRP) are associated with incident hypertension as well as cardiovascular events, and angiotensin II is a potent proinflammatory mediator. However, whether angiotensin receptor blockade lowers hsCRP is uncertain. We performed a randomized trial in which 1668 patients with stage 2 hypertension were treated with 160 mg

valsartan or 160/12.5 mg valsartan/hydrochlorothiazide (HCTZ) once daily for 2 weeks with forced titration to 320 mg valsartan or 320/12.5 mg valsartan/HCTZ for an additional 4 weeks. After 6 weeks, systolic blood pressure (–25 versus –18 mm Hg; P<0.001) and diastolic blood pressure (–14 versus –9 mm Hg; P<0.001) were reduced to a greater degree among those allocated to valsartan/HCTZ than to valsartan monotherapy. The median change in hsCRP was –0.12 mg/L among those allocated to valsartan compared with +0.05 mg/L among those allocated to valsartan/HCTZ, a 13.3% difference (P<0.001); this difference between valsartan and valsartan/HCTZ was present in all subgroups evaluated despite the fact that blood pressure reduction was greater in the combined therapy group. No relationship was observed between hsCRP reduction and blood pressure; in all analyses, the proportion of variation in change in hsCRP with valsartan monotherapy explained by change in blood pressure was <2%. Thus, in this prospective trial, valsartan reduced hsCRP levels in a manner independent of degree of blood pressure reduction. These data raise the hypothesis that angiotensin

receptor blockade may have anti-inflammatory effects in addition to blood pressure–lowering effects.

AT1 receptor activation

Braz J Med Biol Res. 2002 Sep;35(9):1001-15. Epub 2002 Aug 30. Recent advances in angiotensin II signaling.Touyz RM, Berry C. Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada. touyzr@ircm.qc.ca Angiotensin II (Ang II) is a multifunctional hormone that influences the function of cardiovascular cells through a complex series of intracellular signaling events initiated by the interaction of Ang II with AT1 and AT2 receptors.

AT1 receptor activation leads to cell growth, vascular contraction, inflammatory responses and salt and water retention, whereas AT2 receptors induce apoptosis, vasodilation and natriuresis. These effects are mediated via complex, interacting signaling pathways involving stimulation of PLC and Ca2+ mobilization; activation of PLD, PLA2, PKC, MAP kinases and NAD(P)H oxidase, and stimulation of gene transcription. In addition, Ang II activates many intracellular tyrosine kinases that play a role in growth signaling and inflammation, such as Src, Pyk2, p130Cas, FAK and JAK/STAT. These events may be direct or indirect via transactivation of tyrosine kinase receptors, including PDGFR, EGFR and IGFR.

Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of Ang receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways may be pivotal in structural and functional abnormalities that underlie pathological processes in cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis.

Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis.

Candido R, Allen TJ, Lassila M, Cao Z, Thallas V, Cooper ME, Jandeleit-Dahm KA. Vascular Division, Baker Heart Research Institute, PO Box 6492, Melbourne 8008,

Victoria, Australia.BACKGROUND: It remains controversial whether specific blockade of the renin-

angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection. METHODS AND RESULTS: Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT1 receptor expression, cellular proliferation, collagen content, macrophage- and alpha-smooth muscle actin-positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments.

CONCLUSIONS: Diabetes-associated atherosclerosis is ameliorated by AT1 receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.

Markers of Inflammation in Diabetes

Diabetes Care. 2006 Aug;29(8):1902-8. Diabetes, Hyperglycemia, and Inflammation in Older Individuals: The Health, Aging and Body Composition study.de Rekeneire N, Peila R, Ding J, Colbert LH, Visser M, Shorr RI, Kritchevsky SB, Kuller LH, Strotmeyer ES, Schwartz AV, Vellas B, Harris TB. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Gateway Building, Suite 3C-309, 7201 Wisconsin Ave., Bethesda, MD 20892-9205. rekenein@nia.nih.gov.

OBJECTIVE: The objective of this study was to assess the association of inflammation with hyperglycemia (impaired fasting glucose [IFG]/impaired glucose tolerance [IGT]) and diabetes in older individuals. RESEARCH DESIGN AND METHODS: Baseline data from the Health, Aging and Body Composition study included 3,075 well-functioning black and white participants, aged 70-79 years.

RESULTS: Of the participants, 24% had diabetes and 29% had IFG/IGT at baseline. C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels (P < 0.001) were significantly higher among diabetic participants and those with IFG/IGT. Odds of elevated IL-6 and TNF-alpha (>75th percentile) were, respectively, 1.95 (95% CI 1.56-2.44) and 1.88 (1.51-2.35) for diabetic participants and 1.51 (1.21-1.87) and 1.14 (0.92-1.42) for those with IFG/IGT after adjustment for age, sex, race, smoking, alcohol intake, education, and study site. Odds ratios for elevated CRP were 2.90 (2.13-3.95) and 1.45 (1.03-2.04) for diabetic women and men and 1.33 (1.07-1.69) for those with IFG/IGT regardless of sex. After adjustment for obesity, fat distribution, and inflammation-related conditions, IL-6 remained significantly related to both diabetes and IFG/IGT. CRP in women and TNF-alpha in both sexes were significantly related to diabetes, respectively, whereas risk estimates for IFG/IGT were decreased by adjustment for adiposity. Among diabetic participants, higher levels of HbA(1c) were associated with higher levels of all three markers of inflammation, but only CRP remained significant after full adjustment. CONCLUSIONS: Our findings show that dysglycemia is associated with inflammation, and this relationship, although consistent in diabetic individuals, also extends to those with IFG/IGT.

Association of high-sensitive C-reactive protein with advanced stage beta-cell dysfunction and insulin resistance in patients with type 2 diabetes mellitus.

Pfutzner A, Standl E, Strotmann HJ, Schulze J, Hohberg C, Lubben G, Pahler S, Schondorf T, Forst T.

Institute for Clinical Research and Development, IKFE GmbH, Parcusstrasse 8, 55116 Mainz, Germany. andreasp@ikfe.de

BACKGROUND: Type 2 diabetes mellitus is associated with increased cardiovascular risk. One laboratory marker for cardiovascular risk assessment is high-sensitivity C-reactive protein (hsCRP).

METHODS: This cross-sectional study attempted to analyze the association of hsCRP levels with insulin resistance, beta-cell dysfunction and macrovascular disease in 4270 non-insulin-treated patients with type 2 diabetes [2146 male, 2124 female; mean age +/-SD, 63.9+/-11.1 years; body mass index (BMI) 30.1+/-5.5 kg/m(2); disease duration 5.4+/-5.6 years; hemoglobin A(1c) (HbA(1c)) 6.8+/-1.3%]. It consisted of a single morning visit with collection of a fasting blood sample. Observational parameters included several clinical scores and laboratory biomarkers.

RESULTS: Stratification into cardiovascular risk groups according to hsCRP levels revealed that 934 patients had low risk (hsCRP <1 mg/L), 1369 patients had intermediate risk (hsCRP 1-3 mg/L), 1352 patients had high risk (hsCRP >3-10 mg/L), and 610 patients had unspecific hsCRP elevation (>10 mg/L). Increased hsCRP levels were associated with other indicators of diabetes-related cardiovascular risk (homeostatic model assessment, intact proinsulin, insulin, BMI, beta-cell dysfunction, all p<0.001), but showed no correlation with disease duration or glucose control. The majority of the patients were treated with diet (34.1%; hsCRP levels 2.85+/-2.39 mg/L) or metformin monotherapy (21.1%; 2.95+/-2.50 mg/L hsCRP). The highest hsCRP levels were observed in patients treated with sulfonylurea (17.0%; 3.00+/-2.43 mg/L).

CONCLUSIONS: Our results indicate that hsCRP may be used as a cardiovascular risk marker in patients with type 2 diabetes mellitus and should be evaluated in further prospective studies.

High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus.

Pfutzner A, Forst T. University of Applied Sciences, Rheinbach, Germany. AndreasP@ikfe.deC-reactive protein (CRP) is a liver-derived pattern recognition molecule that is increased in

inflammatory states. It rapidly increases within hours after tissue injury, and it is suggested that it is part of the innate immune system and contributes to host defense. Since cardiovascular disease is at least in part an inflammatory process, CRP has been investigated in the context of arteriosclerosis and subsequent vascular disorders. Based on multiple epidemiological and intervention studies, minor CRP elevation [high-sensitivity CRP (hsCRP)] has been shown to be associated with future major cardiovascular risk (hsCRP:<1 mg/L=low risk; 1-3 mg/L=intermediate risk; 3-10 mg/L=high risk; >10 mg/L=unspecific elevation). It is recommended by the American Heart Association that patients at intermediate or high risk of coronary heart disease may benefit from measurement of hsCRP with regard to their individual risk prediction. Elevation of hsCRP is associated with increased risk of type 2 diabetes development in patients with all levels of metabolic syndrome. In type 1 and type 2 diabetes mellitus, hemoglobin A1c significantly correlates with hsCRP levels and future cardiovascular risk. Also, hsCRP levels increase with the stage of beta-cell dysfunction and insulin resistance. Non-diabetes drugs that have been shown to reduce hsCRP concentrations include aspirin, statins, cyclooxygenase-2 inhibitors, and fibrates. Recent intervention studies have also demonstrated the distinct efficacy of different anti-diabetes treatments on a variety of cardiovascular risk markers. Intensive insulin therapy may reduce inflammation, but this effect may be influenced by the degree of weight gain. Treatment with peroxisome proliferator-activated receptor gamma has lead to substantial reduction of hsCRP and other cardiovascular risk markers in several comparator studies. Since this effect was shown to be independent of the degree of glycemic improvement, it can be regarded as a classspecific effect. Whether these findings translate into a reduction of overall cardiovascular mortality will soon be shown by the currently running thiazolidinedione outcome studies. Positive results in these trials will further strengthen the value and acceptance of hsCRP, which is recommended as a predictive laboratory marker for cardiovascular disease risk also in patients with diabetes mellitus.

Oxidative stress, inflammation and autoimmune reaction in type 1 and type 2 diabetes mellitus.

Kalousova M, Fialova L, Skrha J, Zima T, Soukupova J, Malbohan IM, Stipek S. Institute of Medical Biochemistry, Charles University, and General Teaching

Hospital, Prague, Czech Republic. mkalousova@hotmail.comDiabetes mellitus (DM) is associated with oxidative stress, elevation of

inflammatory markers and other mechanisms, which may contribute to accelerated atherosclerosis. The aim of the study was to determine prominent factors of these pathogenic processes in patients with DM, to examine their relationship in serum, and to find out the differences between DM1 and DM2. Advanced oxidation protein products (AOPP), C-reactive protein (CRP), pregnancy-associated plasma protein-A (PAPP-A), anticardiolipin antibodies (ACA) and anti-beta2-glycoprotein-1 antibodies (anti-beta2-GPI) were determined in 27 patients with DM1, 27 patients with DM2 and 23 healthy subjects. AOPP, CRP and anti-beta2-GPI were significantly elevated in DM2 in comparison with healthy subjects (p<0.01, p<0.0001, p<0.0001, respectively). In DM1, anti-beta2-GPI were elevated (p<0.0001) as well, but there was no increase of either AOPP or CRP. There was no difference in PAPP-A levels in DM1 or DM2 and healthy subjects. In DM 1, AOPP correlate significantly with anti-beta2-GPI (r = 0.68, p<0.05). In DM2, there is a significant correlation between anti-beta2-GPI and PAPP-A (r=0.45, p<0.05).

Oxidative stress and inflammation are more expressed in DM2 and they are partly related. In DM1, oxidative stress seems to be in closer link to autoimmune reaction than to inflammation.

A generalised disturbance of vascular endothelial cell function

Diabetes is associated with a high incidence of endothelial-binding antibodies which do not correlate with retinopathy, von Willebrand factor, angiotensin-converting enzyme or C-reactive protein.

Diabetes Res. 1991 Jul;17(3):115-23. Petty RG, Pottinger BE, Greenwood RM, Pearson JD, Mahler RF.

Section of Vascular Biology, M.R.C. Clinical Research Centre, Harrow, UK.Increasing evidence implicates endothelial cell dysfunction in the development of

diabetic microvascular disease, but its precise nature is elusive. This study sought to extend previous observations on the association between diabetes and the endothelial cell-derived glycoprotein von Willebrand factor (vWF), in a study of 777 diabetic patients. Compared with a mean of 1.07 +/- 0.18 iu/ml in a non-diabetic population, vWF was found to be elevated to 1.59 +/- 0.14 iu/ml in the whole sample, but particularly in those with retinopathy or microalbuminuria. It was studied whether such an elevation is part of an acute phase response, or is accompanied by other indicators of endothelial cell dysfunction. Plasma samples were examined for vWF, and serum for angiotensin converting enzyme (ACE), C-Reactive protein (CRP), IgG and IgM endothelial cell-binding antibodies (anti-EC Ig). A strong positive association was found (p less than 0.005) between the extent of elevation of vWF and the presence of diabetic retinopathy. ACE and CRP were rarely raised, and their levels did not correlate with either diabetic retinopathy or vWF levels.

However, 52% of the patients had circulating anti-EC IgG or IgM, although their presence did not correlate with retinopathy, or with vWF, ACE or CRP.

Thus diabetic retinopathy and probably nephropathy is associated with a specific but generalised disturbance of vascular endothelial cell function

C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle

Circulation. 2003;107:1783.Chao-Hung Wang, MD; Shu-Hong Li, MSc; Richard D. Weisel, MD; Paul W.M. Fedak, MD; Aaron S. Dumont, MD; Paul Szmitko, BSc; Ren-Ke Li, MD, PhD; Donald A.G. Mickle, MD; Subodh Verma, MD, PhD From the Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada, and the Division of Neurosurgery (A.S.D.), UVA Department of Neurosurgery, Charlottesville, Va. Background— Accumulating evidence suggests that C-reactive protein (CRP), in addition to predicting vascular disease, may actively facilitate lesion formation by inciting endothelial cell activation. Given the central importance of angiotensin type 1 receptor (AT1-R) in the pathogenesis of atherosclerosis, we examined the effects of CRP on AT1-R expression and kinetics in vascular smooth muscle (VSM) cells. In addition, the effects of CRP on VSM migration, proliferation, and reactive oxygen species (ROS) production were evaluated in the presence and absence of the angiotensin receptor blocker, losartan. Lastly, the effects of CRP (and losartan) on neointimal formation were examined in vivo in a rat carotid angioplasty model. Methods and Results— The effects of human recombinant CRP (0 to 100 µg/mL) on AT1-R transcript, mRNA stability, and protein expression were studied in cultured human VSM cells. AT1-R binding was assessed with 125I-labeled angiotensin II (Ang II). VSM migration was assessed with wound cell migration assays, whereas VSM proliferation was determined with [3H]-incorporation and cell number. The effects of CRP (and losartan) on Ang II–induced ROS production were evaluated by 2',7'-dichlorofluorescein fluorescence. Lastly, the effects of CRP (and losartan) on neointimal formation, VSM cell migration, proliferation, and matrix formation were studied in vivo in a rat carotid artery balloon injury model. CRP markedly upregulated AT1-R mRNA and protein expression and increased AT1-R number on VSM cells. CRP promoted VSM migration and proliferation in vitro and increased ROS production. Furthermore, CRP potentiated the effects of Ang II on these processes. In the rat carotid artery angioplasty model, exposure to CRP resulted in an increase in cell migration and proliferation, collagen and elastin content, and AT1-R expression, as well as an increase in neointimal formation; these effects were attenuated by losartan. Conclusions— CRP, at concentrations known to predict cardiovascular events, upregulates AT1-R–mediated atherosclerotic events in vascular smooth muscle in vitro and in vivo. These data lend credence to the notion that CRP functions as a proatherosclerotic factor as well as a powerful risk marker.

Airborne particulate matter elevates CRP, IL6; especially in DM & HTN

Environ Health Perspect. 2006 Jul;114(7):992-8. Diabetes, obesity, and hypertension may enhance associations between air pollution and markers of systemic inflammation.Dubowsky SD, Suh H, Schwartz J, Coull BA, Gold DR. Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA. dubowsky@u.washington.edu Airborne particulate matter (PM) may lead to increased cardiac risk through an inflammatory pathway. Therefore, we investigated associations between ambient PM and markers of systemic inflammation among repeated measures from 44 senior citizens (>/= 60 years of age) and examined susceptibility by conditions linked to chronic inflammation. Mixed models were used to identify associations between concentrations of fine PM [aerodynamic diameter </= 2.5 microm (PM2.5)] averaged over 1-7 days and measures of C-reactive protein (CRP) , interleukin-6 (IL-6) , and white blood cells (WBCs) . Effect modification was investigated for diabetes, obesity, hypertension, and elevated mean inflammatory markers. We found positive associations between longer moving averages of PM2.5 and WBCs across all participants, with a 5.5% [95% confidence interval (CI) , 0.10 to 11%] increase per interquartile increase (5.4 microg/m3) of PM2.5 averaged over the previous week. PM2.5 and CRP also exhibited positive associations among all individuals for averages longer than 1 day, with the largest associations for persons with diabetes, obesity, and hypertension. For example, an interquartile increase in the 5-day mean PM)2.5 (6.1 microg/m3) was associated with a 14% increase in CRP (95% CI, -5.4 to 37%) for all individuals and an 81% (95% CI, 21 to 172%) increase for persons with diabetes, obesity, and hypertension. Persons with diabetes, obesity, and hypertension also exhibited positive associations between PM2.5 and IL-6. Individuals with elevated mean inflammatory markers exhibited enhanced associations with CRP, IL-6, and WBCs. We found modest positive associations between PM2.5 and indicators of systemic inflammation, with larger associations suggested for individuals with diabetes, obesity, hypertension, and elevated mean inflammatory markers.

Diabetes in survivors of bone marrow transplantation

J Pediatr Hematol Oncol. 2004 Feb;26(2):81-90. Diabetes mellitus in long-term survivors of pediatric hematopoietic cell transplantation. Hoffmeister PA, Storer BE, Sanders JE. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. To identify risk factors associated with the development of diabetes mellitus and to describe the prevalence of diabetes in pediatric hematopoietic cell transplant (HCT) survivors. The follow-up records of 748 patients who survived for at least 2 years after pediatric HCT were retrospectively reviewed for diagnosis of diabetes. Risk factors for type 2 diabetes were analyzed using multivariate statistics. Among 748 patients with a median of 11 years of follow-up, 38 developed diabetes after HCT. Four patients (three leukemia and one neuroblastoma) developed type 1 diabetes 8 to 14 years after HCT, at between 10 and 19 years of age. Thirty-four patients (32 leukemia and 2 aplastic anemia) developed type 2 diabetes 1 to 24 years after HCT, at between 11 and 41 years of age. Of the 34 patients with type 2 diabetes, 23 were non-Hispanic white, 3 had experienced asparaginase toxicity (hyperglycemia and/or pancreatitis), and 26 had a family history of diabetes. Risk factors associated with type 2 diabetes were diagnosis of acute or chronic leukemia, race/ethnicity other than non-Hispanic white, family history of diabetes, and asparaginase toxicity. The prevalence of type 1 diabetes among all surviving patients was 0.52%, or three times higher than the general U.S. population. The prevalence of type 2 diabetes was 9% among leukemia survivors and 2% among aplastic anemia survivors, both higher than expected. Pediatric HCT survivors are more likely to develop diabetes than the general population.

β-Cell Mass Defines Therapy

Regardless of the Etiology of the Diabetic State

The Lancet 2001; 358:221-229Type 1 diabetes: new perspectives on disease pathogenesis and treatment

Mark A Atkinson   and   George S Eisenbarth 

.

Beta Cell Mass Declines with Severity of DMFigure 1. Immunohistochemical analysis of PCNA and insulin in pancreatic tissue from

non-diabetic rats (A),

type 2 diabetic rats (B)

and type 1 diabetic rats (C). Arrows indicate PCNA-stained beta cells in islets.

Extra-islet beta cells localized in pancreatic ducts from type 2 diabetic rats (D). Magnification x630. 

JOP. J Pancreas (Online) 2004; 5(6):464-475.Cholecystokinin Octapeptide: A Potential Growth Factor for Pancreatic Beta Cells in Diabetic RatsEmmanuelle Kuntz, Michel Pinget, Christiane DamgéEuropean Center for Study of Diabetes, Faculty of Medicine, Strasbourg, France

Match Therapy to β-cell mass estimated by pattern on graphing readings from home

glucometer. (Assume normal renal function)A. Once serum glucose normalized, change therapy to oral agents. Maintenance TZD therapy. With early intervention remission common.

B. Oral agents or glargine insulin + TZD. Remission possible but takes longer to induce.

C. Very difficult to normalize blood sugar due to low endogenous insulin output, loss of autoregulation of β-cells, and loss of feedback mechanisms with α-cells. This is the group of patients that require “basal” glargine insulin and two injections of Humalog (breakfast and dinner) daily (twice daily nateglinide may be substituted for Humalog in certain cases). In renal insufficiency, nateglinide (Starlix) may be useful since it is catabolized in the liver. TZD therapy can reduce dependence on insulin. This will usually work in Type 1 diabetics and “burned out” Type 2. Avoid Metformin or other agents (e.g. atypical antipsychotics) with potential to precipitate ketacidosis.

Male   Age 49 Weight 475 lbs. Duration of DM approx. 3 yrs.

Prior Rx. Actos 15 mg daily and Metformin. Current meds: Actos 45 mg daily and Lantus insulin 24 units q AM. Initial HbA1c in 1/03 13.3.   12/14/04  6.4

Female  Age 49Duration of DM 4 yrs. Highest BS over 466 Low about 101. Cr 0.9  Never

hospitalized for DM.Prior Rx. Avandamet 4/500 daily.

Current meds Lantus 20 units s.c. q AM and Actos 45 mg daily.HbA1c. 11.6  9/12/2005

Female    Age 47Duration of DM 17 yrs.  Highest BS over 500.Frequent hypoglycemia before as low as 37 mg%.Cr 1.3. Diabetic foot ulcer. No MI or CVA.Prior Rx. Sliding scale insulin. with Lantus 100 units.  Also used70/30 in past.Current meds: Lantus 50 units daily and Actos 45 mg daily.10/14/05 HbA1c 8.5

Vigilant and Frequent Changes of Diabetic Therapy

Treatment should change with estimate of beta cell mass in every patient. Although C-Peptide can be measured, the most convenient way to gauge this is by using the Standard Deviation from the Home Glucose Meter. Insulin dose or doses of oral medication should be increased or decreased step-wise depending upon the S.D. , hyperglycemic or hypoglycemic readings.

Initiation Phase Control Phase Remission Phase

Increase insulin by 5-10 units daily Decrease insulin by 5-10 units daily

(If patient requires insulin, has normal renal function and is on glargine insulin (Lantus®))

A Closer Look at Hypoglycemia

"We no longer try to get the Hemoglobin A1C below 9 in our elderly patients. We just saw too many falls (caused by

tight control) "

Ray Plodkowski M.D. Chief of Endocrinology and Metabolism, Reno Veterans Hospital, University of Nevada.

(Personal communication 11/11/03 Yuba City)

Hypoglycemia and the Brain

The first topic addressed at the meeting focused on hypoglycemia and the brain. Glucose is virtually the sole fuel for the adult brain, and its use is coupled tightly to neuronal activation. In newborns, the central nervous system accounts for about 90 percent of the body's glucose. Depriving the brain of glucose, such as occurs during hypoglycemia in diabetes, can have a profound impact. Scientists are now beginning to unravel the consequences of hypoglycemia on brain function and seeking ways to protect the brain from this frightening disorder. The speakers noted that glial cells in the brain are involved in coupling neuronal activation to glucose utilization. These cells are located near capillaries through which glucose is transported from blood to the brain.

Scientists have also learned that certain neurons in the brain, in particular those found in a region called the hypothalamus, can specifically sense glucose. These neurons are classified as either glucose responsive (increased rate of neuronal activation as glucose levels increase) or glucose sensitive (decreased rate of neuronal firing as glucose levels increase). Such neurons may have key molecular features in common with insulin-secreting beta cells that make the neurons glucose responsive/sensitive"

From the Symposium "Hypoglycemia 2001: From Research to Practice. Assisi, Italy.

The impact of recurrent hypoglycemia on cognitive function in aging.

Neurobiol Aging. 2005 Oct 14; McNay EC. Section of Endocrinology, Yale University School of Medicine, TAC S147, One Gilbert Street, New Haven, CT 06519, USA.

The decline in cognitive function, especially on challenging tasks, associated with aging is well known and relatively well-characterised. Recent evidence has provided strong support for the view that reduced ability to provide and regulate fuel supply, i.e., glucose, to the aged brain is a major cause of such decline. Inability to regulate glucose also defines diabetes, and both diabetes and the recurrent hypoglycemia seen in intensively insulin-treated diabetic patients also affect cognition. Recent data on the interaction between such recurrent hypoglycemia and aging in modulating cognition is reviewed, and the insights gained into mechanisms of age-related cognitive decline discussed.

Frequent use of Glucose Pills are a sign of a poor approach to the treatment of

DM.

IMPACT OF HYPOGLYCEMIA ON QUALITY OF LIFE

Curr Med Res Opin. 2005 Sep;21(9):1477-83. Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes. Davis RE, Morrissey M, Peters JR, Wittrup-Jensen K, Kennedy-Martin T, Currie CJ. School of Care Sciences, University of Glamorgan, Pontypridd, Wales, United Kingdom. AIM: To characterise the impact of increasing severity and frequency of hypoglycaemia on utility, quality of life, primary care resource use and productivity (time away from normal activities) in people with both Type 1 and Type 2 diabetes. METHODS: A postal survey was sent to 3200 people with diabetes. Self-reported episodes of mild, moderate, severe and nocturnal hypoglycaemia were quantified from a list of signs and symptoms. A number of instruments were used to explore the effect of frequency and severity of hypoglycaemia on quality of life and productivity. RESULTS: There were 861 respondents for whom diabetes type was identifiable. Of these respondents, 629 (73%) experienced some form of hypoglycaemia, 516 (60%) non-exclusively experienced mild or moderate hypoglycaemia, 57 (7%) experienced severe hypoglycaemia and 191 (22%) experienced nocturnal hypoglycaemia. Quality of life and health-related utility decreased as the frequency and severity of hypoglycaemia increased. The use of primary care resources and lost productivity increased as the severity and frequency of hypoglycaemia increased. These associations were independent in multivariate analysis. CONCLUSIONS: These findings suggest hypoglycaemia impacts heavily on the well-being, productivity and quality of life of people with diabetes, and that every effort should be made to minimise hypoglycaemia while aiming for good glycaemic control.

Case of Tight Control and Seizures

Walter H. 30 y.o. Type 2 DM male placed in NPH insulin twice daily; 25 units in the AM, and 20 units in the PM. In 7/2000 he was on 20 NPH in the AM and 10 R twice daily. Patient and wife relate that his blood sugar fell below 25 on at least three occasions (once to 14 mg%) precipitating a seizure on each occasion and ambulance transportation to the Emergency Department on both these occasions. His physician advised him to carry sugar pills. No HbA1C done in over 2 years.

Doing the Math

In the DCCT study 119 patients of a total of 817 had at least one episode of hypoglycemia resulting in coma or seizure. Most of these were due to “Tight Control” (15%).

Assume 17 million diabetics in the US. Further assume that 33% of these are on tight control insulin. (5,610,000).

Therefore, 1,626,900 suffer seizures or coma from “Tight Control” therapy yearly.

Annual DeathsFrom Tight Control

Estimated number of deaths from “Tight Control” 37,408

Number of fatalities in 2001 from passenger car accidents in the U.S.

20,233*

* Passenger Car Occupant Safety Data – US Dept. of Transportation

Adverse outcomes of Tight Control – Increasing incidence of Hypoglycemic Coma in Children

with IDDM. Diabetes Care,Vol. 14, No. 11, November 1991. Egger, M. et al.

– Hypoglycemia-Induced Autonomic Failure in Insulin-Dependent Diabetes Mellitus. Proceedings of the Association of American Physicians 107:1 April 1995. Cryer, P.

– Iatrogenic Hypoglycemia as a Cause of Hypoglycemia-Associated Autonomic Failure in IDDM. Diabetes, Vol 41, March 1992.Cryer P.

– Intermittent Hypoglycemia Impairs Glucose Counterregulation. Diabetes, Vol 41, December 1992. Widom B., and Simonson D.

– Frequency of Severe Hypoglycemia in Patients with Impaired Awareness of Hypoglycemia. Diabetes Care, Vol. 17, Number 7, July 1994. Gold A., et al.

Adverse outcomes of Tight Control – Recurrent hypoglycemia hemiparesis and

aphasia in an adolescent patient. Pediatr Neurol 2001 May; 24(5):385-6. Kossoff EH, Ichord RN, Bergin AM.

– Hemiplegia hypoglycemia syndrome. Eur J Emerg Med. June 1999:6(2):157-9. Vanpree D, Donckier J, Gillet JB.

– Hypoglycemia and cognitive function in diabetes. Sept. 2001. (123):30-7. Frier BM.

Adverse outcomes of Tight Control

– Hypoglycemia-Induced Cognitive Dysfunction in Diabetes Mellitus: Effect of Hypoglycemia Unawareness. Physiology & Behavior. Vol 58, No. 3, pp 501-511, 1995.

– Severe Hypoglycemia and Intelligence in Adult Patients with Insulin-Treated Diabetes. Diabetes. Vol. 42 February 1993. Deary, I.J. et al.

– Epinephrine Secretion, Hypoglycemia Unawareness, and Diabetic Autonomic Neuropathy. Ann Intern Med. 1994:120:512-517. Hoeldtke, R.D. et al.

– Unawareness of Hypoglycemia by Insulin-Dependent Diabetics. Horm.metabol. Res. 22(1990) 90-95. Grimaldi A., et al.

Adverse Effects of Tight Control Tissue evidence of Injury

Impaired glucagon release secondary to hypoglycemia. (diabetic BB rats) Metabolism 1996 Nov;45(11):1422-6

Direct injury to neurons. – Hypoglycemia is a cause of axonal injury.

Neuropathol Appl Neurobiol 2000 Oct 26 (5):448-53 Dolinak D., et al

– Specific changes in human brain after hypoglycemic injury. Stroke 1997 Mar:28(3):584-7 Fujioka M., et al.

Oligodendroglia

Cells of the CNS include neurons, glia, and microglia. Neurons have many ribosomes, since they synthesize proteins and other substances very actively. Generally, neurons do not divide, although recent research indicates that there may be some limited capacity for division in post-natal life. The neurons are composed of a cell body, dendrites, which receive signals, and an axon. The axon may be very long and culminates in synaptic processes that release neurotransmitters. The axon is surrounded by a sheath of myelin, which insulates the axon and makes transmission of nerve impulses much more efficient. The axon also contains neurofilaments and microtubules, both of which serve an essential role in transport of substances through the neuron. Glia include astrocytes and oligodendroglia. Astrocytes are so named because they look like stars. They may react to disease processes by forming scar tissue. They have a metabolic relationship with neurons, and they contribute to the “blood-brain barrier,” which makes it more difficult for blood-borne substances to enter the brain than other bodily tissues.

The oligodendroglia form myelin in the white matter. In the gray matter,they are “satellite cells” that “hug” the neurons. The gray matter of

the CNSconsists of cells bodies; the white matter contains many axons,

which arewhite due to the insulating myelin. Microglia are macrophages that

reside inthe nervous system. They are usually not very apparent in a healthy

brain.

Oligodendroglia are more susceptible to oxidative stress

Neurosci Biobehav Rev. 1997 Mar;21(2):151-66. Related Articles, Links Response of glial cells to ischemia: roles of reactive oxygen species and glutathione. Juurlink BH. Saskatchewan Stroke Research Centre, Saskatoon, Canada.

A review of reactive oxygen species (ROS) is followed by a discussion on the differential susceptibility of astrocytes and oligodendroglia to ischemia-related insults. Astrocytes can survive chronic hypoxia as well as long periods of simulated ischemia, i.e. hypoglycemia and anoxia.

Oligodendroglia are preferentially injured over astrocytes by chronic hypoxia, reperfusion following ischemia, hypoglycemia or uncoupling of oxidative phosphorylation. Increasing the generation of ROS in mixed glial cultures by adding ROS generators results in preferential death of oligodendroglia.

Oligodendroglia are more susceptible to oxidative stress because they have low glutathione contents while concomitantly having higher iron contents and are more dependent upon oxidative phosphorylation than are astrocytes. Glutathione plays a pivotal role in the ROS-scavenging strategies of the cell while iron plays a pivotal role in the generation of hydroxyl, peroxy and akoxy radicals. These in vitro findings delineate the physiological basis for the white matter damage seen in adults following prolonged periods of hypoperfusion and the damage seen in the oligodendroglial germinal zones resulting in periventricular leukomalacia seen following in utero hypoxia-ischemia.

Periventricular white matter injury in rats made hypoglycemic with insulin

Acta Neuropathol (Berl). 1984;64(3):177-91. The distribution of hypoglycemic brain damage. Auer RN, Wieloch T, Olsson Y, Siesjo

BK.

Rats were exposed to insulin-induced hypoglycemia resulting in periods of cerebral isoelectricity ranging from 10 to 60 min. After recovery with glucose, they were allowed to wake up and survive for 1 week. Control rats were recovered at the stage of EEG slowing. After sub-serial sectioning, the number and distribution of dying neurons was assessed in each brain region. Acid fuchsin was found to stain moribund neurons a brilliant red. Brains from control rats showed no dying neurons. From 10 to 60 min of cerebral isoelectricity, the number of dying neurons per brain correlated positively with the number of minutes of cerebral isoelectricity up to the maximum examined period of 60 min.

Neuronal necrosis was found in the major brain regions vulnerable to several different insults. However, within each region the damage was not distributed as observed in ischemia. A superficial to deep gradient in the density of neuronal necrosis was seen in the cerebral cortex. More severe damage revealed a gradient in relation to the subjacent white matter as well. The caudatoputamen was involved more heavily near the white matter, and in more severely affected animals near the angle of the lateral ventricle. The hippocampus showed dense neuronal necrosis at the crest of the dentate gyrus and a gradient of increasing selective neuronal necrosis medially in CA1. The CA3 zone, while relatively resistant, showed neuronal necrosis in relation to the lateral ventricle in animals with hydrocephalus. Sharp demarcations between normal and damaged neuropil were found in the hippocampus. The periventricular amygdaloid nuclei showed damage closest to the lateral ventricles. The cerebellum was affected first near the foramina of Luschka, with damage occurring over the hemispheres in more severely affected animals. Purkinje cells were affected first, but basket cells were damaged as well. Rare necrotic neurons were seen in brain stem nuclei. The spinal cord showed necrosis of neurons in all areas of the gray matter. Infarction was not seen in this study. The possibility is discussed that a neurotoxic substance borne in the tissue fluid and cerebrospinal fluid (CSF) contributes to the pathogenesis of neuronal necrosis in hypoglycemic brain damage.

Recurrent severe hypoglycemia and MRI changes in humansDiabetes Care. 1997 Jun;20(6):1013-8.

Brain abnormalities demonstrated by magnetic resonance imaging in adult IDDM patients with and without a history of recurrent severe hypoglycemia. Perros P, Deary IJ, Sellar RJ, Best JJ, Frier BM. Department of Diabetes, Royal Infirmary of Edinburgh, U.K. OBJECTIVE: Previous studies of a cohort of 100 patients with IDDM have shown that a history of recurrent severe hypoglycemia is associated with a modest impairment of cognitive function. The aim of the present study was to determine whether IDDM patients with and without a history of severe hypoglycemia have lesions in the brain that are identifiable by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) and to investigate the putative relationship of any structural brain abnormalities with cognitive function. RESEARCH DESIGN AND METHODS: MRI and MRS of the brain were performed in 22 patients from the original cohort. Eleven IDDM patients with no history of severe hypoglycemia (group A) were compared with 11 IDDM patients who had a history of five or more episodes of severe hypoglycemia (group B). RESULTS: Nine patients (41%) had abnormal scans. Two types of abnormalities were observed: high-intensity rounded lesions, > 3 mm in diameters, distributed in the periventricular white matter (leukoaraiosis) in four patients; and cortical atrophy in five patients. Five patients in group B had cortical atrophy, whereas no patient in group A demonstrated this feature (P < 0.05). MRS of the frontal and parietal lobes showed no differences in the N-acetyl aspartate/creatine or N-acetyl aspartate/choline ratios between groups A and B. Patients with cortical atrophy showed a nonsignificant trend toward reduced performance on Rapid Visual Information Processing. CONCLUSIONS: Brain abnormalities demonstrated by MRI are common in patients with IDDM of long duration and are suggestive of premature aging of the brain. IDDM per se may be an important pathogenic factor, but a significant association was observed between a history of recurrent severe hypoglycemia and cortical atrophy, which may be related to the modest impairment of cognitive function that has been reported previously.

The cognitive correlates of white matter abnormalities in normal aging

Neuropsychology. 2000 Apr;14(2):224-32. 

The cognitive correlates of white matter abnormalities in normal aging: a quantitative review.

Gunning-Dixon FM, Raz N.

Department of Psychology, University of Memphis, Tennessee 38152-6400, USA.

Cerebral white matter of asymptomatic people frequently exhibits circumscribed areas of hyperintensity on magnetic resonance (MR) images and hypodensity on computed tomography scans. However, behavioral implications of this phenomenon remain unclear. In this meta-analysis, the authors examine cumulative evidence regarding the cognitive sequelae of white matter abnormalities in adults without dementia. The influence of potential moderator variables, such as neuroimaging technique, location of the lesions, rating scale, and demographic characteristics of the sample on the association between the burden of white matter hyperintensities and cognitive performance was also examined. Results indicate that white matter abnormalities observed on MR images are associated with attenuated performance on tasks of processing speed, immediate and delayed memory, executive functions, and indices of global cognitive functioning. There was no significant link between the white matter hyperintensities and psychometric indices of intelligence or fine motor performance.

Specific changes in human brain after hypoglycemic injury.

Stroke. 1997 Mar;28(3):584-7. 

Specific changes in human brain after hypoglycemic injury.

Fujioka M, Okuchi K, Hiramatsu KI, Sakaki T, Sakaguchi S, Ishii Y.

Department of Neurosurgery, Nara Medical University, Japan. RXL00203@niftyserve.or.jp

BACKGROUND AND PURPOSE: Very few reports are available on serial changes in the human brain after severe hypoglycemic injury. The aim of this study was to investigate sequential neuroradiological changes in brains of patients after hypoglycemic coma compared with those after cardiac arrest previously studied with the same methods. METHODS: We repeatedly studied CT scans and MR images obtained at 1.5 T in four vegetative patients after profound hypoglycemia associated with diabetes mellitus. RESULTS: In all patients, consecutive CT scans showed symmetrical, persistent low-density lesions with transient enhancement in the caudate and lenticular nuclei and transient enhancement in the cerebral cortex 7 to 14 days after onset. Serial MR images consistently revealed symmetrical lesions of persistent hyperintensity and hypointensity on T1- and T2-weighted images, respectively, in the caudate and lenticular nuclei, cerebral cortex, substantia nigra, and/or hippocampus from 8 days to 12 months after onset.

CONCLUSIONS: Repeated MR images revealed specific lesions in the bilateral basal ganglia, cerebral cortex, substantia nigra, and hippocampus, which suggests the particular vulnerability of these areas to hypoglycemia in the human brain. We speculate that the localized lesions represent tissue degeneration, including some combination of selective neuronal death, proliferation of astrocytic glial cells, paramagnetic substance deposition, and/or lipid accumulation. The absence of localized hemorrhages on MR images in hypoglycemic encephalopathy is in marked contrast to the presence of regional minor hemorrhages in postischemic-anoxic encephalopathy.

Basal Ganglia

MRI’s of patients subjected to recurrent hypoglycemia

Case 1

MRI of brain - 1/13/03 - showed scattered foci of increased

signal in the periventricular white matter with changes more

prominent on the left. These white matter changes appear to

be chronic.

LOCAL PATIENT WITH BRAIN INJURY FROM HYPOGLYCEMIA

Barbara R. Hx of memory loss for 2 years.

Patient experienced multiple hypoglycemic episodes while on oral hypoglycemic agents.

Barbara R.

Barbara R.

The MRI appearance of hypoglycemia

Case 2

Multiple daily injections of 70/30 insulin. AF and altered mental status

A Middle Aged Male on Multiple injections of 70/30 insulin per day develops AF and recurrent changes in mental status. This one most severe with periods of paresis and unresponsiveness.

Multiple periventricular and subcortical white matter lesions. “Acute/subacute hemorrhagic infarcts” “…less likely due to metastatic disease” Cardiac ECHO: Negative for clot.

Case 3

72 y.o. female with DM x 34 yrs approximately. Multiple hypoglycemic episodes per day for several years.

Profound memory loss and difficulty concentrating.

Reading by Radiologist:

1. Old lacunar infarction in the left basal ganglia and internal capsule.

2. Some chronic ischemic change in the pons and external capsule.

Case 4

Patient D.D.

MRI IMPRESSION by Radiologist:

1. No acute intracranial abnormality seen.

2. Minimal white matter periventricular changes likely related to early small vessel ischemic disease.

3. Mild age-related atrophy.

Patient D.D.

Case 5

Raymond W. 66 y.o. male with chronic atrial fibrillation, peripheral vascular disease, a foot ulcer on right great toe, history of alcoholism, syncope, and recurrent hypoglycemia. He has memory loss and loss of concentration.

HemoglobinA1C history

7/12/00 15.2 Glucophage 1000 mg bid. Humulin N 10 units h.s.

11/07/00 7.5

12/18/02 10.3 70/30 insulin bid 15/18. Sliding scale Novolog insulin

4/28/06 10.1

6/07/06 Lantus insulin 25 units daily. Humalog 15 units twice daily.

Current medications: Lantus 35 units daily. Actos 45 mg daily. Starlix 120 tid.

(Vytorin 10/20. Cymbalta 30 mg, Diovan 160 mg. Lasix 20 mg, Digitek 125 mcg. K suppl.)

Case 5. Raymond W.

Case 5 R.W.

Are there documented adverse macrovascular complications to the ADA/DCCT Tight Control Protocol? What is the Emperor wearing?

Monday, 29 May 2006 An investigative report in The Philadelphia Inquirer examined pharmaceutical company ties to six, tax exempt organziations that identify themselves as “patient advocacy” groups, "Each a leading advocate for patients in a disease area.”  The conflicts of interest are covert: the reporter notes that "although patients seldom know it, many patient groups and drug companies maintain close, multimillion-dollar relationships while disclosing limited or no details about the ties....the groups rarely disclose such ties when commenting or lobbying about donors' drugs. They also tend to be slower to publicize treatment problems than breakthroughs. And few openly questioned drug prices."

The following six organizations took in $29 million in drug company donations last year: American Diabetes Association (ADA); National Alliance on Mental Illness (NAMI); National Gaucher Foundation; Children & Adults with Attention Deficit/Hyperactivity Disorder (CHADD); Arthritis Foundation (AF); National Organization on Rare Diseases (NORD). “For drug companies, patient groups carry credibility that the industry sometimes lacks to target patients and "opinion leaders" who drive prescriptions, and hence, sales.” However, such coziness “raises questions about the impartiality of groups that patients trust for unbiased information.”……………………………………………….The Inquirer reports that The American Diabetes Association privately enlisted an Eli Lilly & Co. executive to chart its growth strategy and write its slogan. It received at least $2.5 million between 2003-2005. And the Inquirer reports that “NAMI, did not disclose that Lilly marketing manager Gerald Radke briefly ran its entire operation. Radke began in 1999 as a Lilly-paid "management consultant," then left Lilly and served as NAMI's paid "interim executive director" until mid-2001. The group acknowledged this only after being shown Radke's resume listing the job.”

“We don’t position ourselves as a watchdog” ADA

Lilly donated at least $3 million to NAMI. For its part, NAMI promotes the increased use of psychotropic drugs, lobbies against any cost-saving restrictions on number of psychotropic drugs prescribed for one patient under Medicaid, and even lobbies for laws allowing mental patients to be forced to take antipsychotic drugs. The drugs most often prescribed for involuntary patients—Janssen’s Risperdal (risperidone) and Lilly’s Zyprexa (olanzapine)—cause debilitating, indeed, lethal effects. . NAMI’s failure to inform its constituents about the danger these drugs pose for patients, and its continued aggressive promotion of these drugs despite the evidence, may be viewed as confirmation that NAMI is an extension of Lilly’s marketing department. The documented hazards:1. During pre-marketing trials 2/3 of patients on Zyprexa dropped out and 1 in 145 died—some committed suicide. http://www.ahrp.org/infomail/0702/12b.php]

2. In 2002, Duke University’s analysis of FDA MedWatch reports identified 289 cases of treatment-emergent diabetes in patients who had been prescribed Zyprexa for less than six months. In addition, the researchers found 100 cases of ketoacidosis (diabetic coma potentially, death) as a result of Zyprexa use, 22 cases of Zyprexa-related pancreatitis, and twenty three patients who died as a result of Zyprexa side effects.  http://www.ahrp.org/infomail/0702/12b.php …………………………………………………..Diabetes is by far the most prevalent serious risk linked to Zyprexa. The fact that NAMI lobbies for laws facilitating involuntary treatment—despite scientific evidence linking the drugs most often used on involuntary patients—is a measure of this organization’s duplicity and betrayal of its mission.

The high incidence of diabetes among patients exposed to Lilly’s antipsychotic drug, Zyprexa, undoubtedly provides the company an opportunity for huge increased profit margins.  Lilly is the foremost producer of treatments for diabetes.

The revelation, discovered during court procedures, that Eli Lilly’s marketing manager, Gerald Radke, actually ran NAMI takes on significance far beyond mere corporate “donations.” Such dubious  direct intermingling between the company marketing manager and a tax exempt organization requires a full investigation by the Inspector General.

  ReferencePHILADELPHIA INQUIRER  Posted on Sun, May. 28, 2006  Donations tie drug firms and nonprofits: Many patient groups reveal few, if any, details on relationships with pharmaceutical donors.By Thomas Ginsberg The American Diabetes Association, a leading patient health group, privately enlisted an Eli Lilly & Co. executive to chart its growth strategy and write its slogan. …….. Jerome Kassirer, a Tufts University and Yale University medical school professor and author of On the Take: How Medicine's Complicity With Big Business Can Endanger Your Health, said better disclosure would guard against abuse. capacity or function, but it also often serves to assist in the career development of the employee," a Lilly spokesman, Edward G. Sagebiel, said. Avoiding favoritism

  "We don't position ourselves as a watchdog," said Bennett of the ADA.The ADA, which received 5 percent to 10 percent of its revenue last year from drug companies, reported little initially in 2004 about suspected diabetes risks from antidepressants. Instead, Tuncer, its spokeswoman, said it convened an expert conference - funded by drug companies - and ended up echoing the concerns. 

Therapy with Metformin and a Sulphonylurea

“The addition of metformin to sulphonylurea was associated with a 96% increased (p=0·039) risk of diabetes-related death. Addition of metformin to sulphonylurea therapy also increased the risk of death from any cause (60% increase, p=0·041). There were no significant differences between the groups for the other aggregate endpoints. In a subgroup analysis, there was no significant difference between patients allocated metformin in addition to chlorpropamide or glibenclamide.”

The Lancet 1998; 352:854-86

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) UK Prospective Diabetes Study (UKPDS) Group

Increased cardiovascular death rate in diabetics treated with “conventional” insulin therapy

Arch Intern Med. 2004 Nov 8;164(20):2273-9. 

Impact of diabetes on mortality in patients with myocardial infarction and left ventricular dysfunction.

Murcia AM, Hennekens CH, Lamas GA, Jimenez-Navarro M, Rouleau JL, Flaker GC, Goldman S, Skali H, Braunwald E, Pfeffer MA.

Mount Sinai Medical Center & Miami Heart Institute, Miami Beach, Fla., USA.

BACKGROUND: Diabetes is a major risk factor for developing coronary heart disease. In patients with diabetes who survived myocardial infarction (MI), less is known about subsequent morbidity and mortality. We evaluated the effects of diabetes in post-MI patients with left ventricular dysfunction on cardiovascular events and death. METHODS: The Survival and Ventricular Enlargement, a randomized, double-blind, placebo-controlled multicenter trial, evaluated the efficacy of captopril vs placebo in 2231 patients following acute MI with left ventricular dysfunction defined as an ejection fraction less than or equal to 40%. Patients were randomly assigned to captopril or placebo 3 to 16 days following MI and were followed up for 2 to 5 years (mean, 3.5 years). RESULTS: Among the 2231, 496 (22.2%) were patients with a history of diabetes, of which 168 (33.9%) were treated with insulin. Patients with diabetes were significantly older; more likely to be women; have a history of prior MI or hypertension; be obese or manifest Killip class II or greater; and have higher systolic blood pressure, pulse pressure, and heart rate, as well as lower ejection fraction. During follow-up, 31.3% of patients with diabetes and 20.1% of nondiabetic patients died (P<.001). Furthermore, 50% of the patients with diabetes had at least 1 major cardiovascular event compared with 32.3% among the nondiabetic patients (P<.001). In multivariate analysis that adjusted for all significant differences in baseline characteristics, patients with diabetes had a 39% higher total mortality (P = .001) and 49% more cardiovascular events (P = .001). Among the patients with diabetes, baseline insulin treatment was associated with a greater risk of death (41.1% vs 26.2%; P = .001) and cardiovascular events (58.3% vs 45.7%; P = .008). CONCLUSIONS: In patients who survived MI with left ventricular dysfunction, diabetes increased risk of death from all causes even after controlling for differences in other risk factors. Patients with diabetes treated with insulin have a particularly higher mortality risk. Patients with diabetes who survived MI with left ventricular dysfunction, in particular those receiving insulin, are at high risk of subsequent mortality and cardiovascular events and thus require intensive risk factor modification, as well as evaluation for novel therapies.

Hemoglogin A1C

Considered alone is never a marker for quality of care of the diabetic patientTo be useful it should only be considered with clinical information about the patientPatients receiving excessive medication can have low (usually with oral meds), normal, or high (usually seen with insulin Rx) HgbA1C values. Patients have been injured and have died while under the care of physicians with “normal” HgbA1C values.

RULE OF THERAPY III

Avoid hypoglycemia.

Aequanimitas

1849 - 1919"Sir William Osler was an ideal physician: a master of the science and art of medicine, a lover of humanity, and totally devoted to healing as a sacred calling."   Michael Bliss, Historian and Author Born in Bond Head, Ontario, Canada in 1849, Sir William Osler achieved international recognition for his revolutionary and progressive approach to medical education and the practice of medicine.ScholarSir William Osler began his medical education at the University of Toronto (1868), completed his training at McGill University (1872), with post graduate studies in London, Vienna, and Berlin.

Be calm! Don’t chase “elevated” blood sugars with insulin; you will do more harm by this.

The serious consequences of hypoglycemia to patient well-being are consistently underestimated and

trivialized by health care providers, …especially by those in academic circles

Remember…neurons metabolize only glucose and oxygen

Defining Diabetes

The Spectrum of DiabetesWho is at risk for DKA?

Type I– Juvenile

Low C-peptide (Low β-cell mass)

Markers of autoimmunity (anti-GAD*, anti-insulin, anti-islet cell)DKA prone

– AdultMarkers of autoimmunity

Low C-peptideNormal HbA1c

DKA proneNo markers of autoimmunity.

Low C-peptide.

Low Hb A1c. DKA prone. ↑ Pancreatic

enzymesNo markers of autoimmunity.

High Hb A1c.

*Glutamic Acid Decarboxylase

Type II– Juvenile

No markers of autoimmunity. Variable Hb A1c

Moderately reduced to Normal C-Peptide (= β-cell mass)

– AdultNo markers of autoimmunity.

Variable Hb A1c.Moderately

reduced to Normal C-Peptide(= β-cell mass)Not DKA prone

No markers of autoimmunity C-Peptide ?High HbA1c.DKA proneHigh rate of

remission

?

Diabetes Mellitus may be the result of:Monogenic autoimmunity. “Type 1” Frequency: Very rare. a) Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) also termed Autoimmune Polyendocrine Syndrome Type 1. (APS-1).Polygenic Type 1 Diabetes. Frequency: Infrequent. More than 30 genes contribute to susceptibility. Wolfram Syndrome. Frequency: Very rare. Autosomal recessive neurodegenerative non-immune IDDM associated with optic atrophy.Abnormal insulins : Frequency: Very rare. 3 reported types …give rise to a substitution of one amino acid of each insulin, resulting in reduced biological activities of these insulins. Pancreatitis. Frequency: Infrequent. This may be the result of toxins (e.g. alcohol) or direct infection by a virus. E.g. congenital rubella infection during the 1st trimester of pregnancy. The virus maintains a “productive infection of the pancreas throughout life.” CMV and rotavirus also suggested. Coeliac disease. Frequency: Rare. Characterized by immune mediated damage to the jejunal mucosa, triggered by gluten (a protein complex in wheat, rye and barley). Genetic susceptibility. Latent Autoimmune Diabetes in Adults (LADA). Frequency: Not infrequent. Slowly progressive autoimmune process resembling “Type 1 DM” but with phenotype of “Type 2”. Susceptible genotypes involved. Islet autoantibodies present. Enteroviral pancreatic infection. Frequency: Epidemic.

A Classical Definition of Diabetes

Dis Markers. 2004;20(3):161-5.  

Update on diabetes mellitus.

Korc M. Division of Endocrinology, Department of Medicine, Dartmouth-Hitchcock Medical Center and Dartmouth Medical School, Hanover, NH 03756, USA. murray.korc@dartmouth.edu

Diabetes mellitus is a complex multi-system disorder that may be classified as autoimmune mediated type 1 diabetes, or as

insulin resistance associated type 2 diabetes. In type 1 diabetes, there is selective loss of the beta cells

within the endocrine islets, as a consequence of T-cell and cytokine mediated destruction of these cells, perhaps in conjunction with destruction of the peri-islet Schwann cells. In type 2 diabetes, the etiology of the resistance ranges from post-receptor defects in the insulin signaling pathway to excessive production of adipocyte derived cytokines that antagonize insulin action to mitochondrial defects that interfere with glucose disposal. Proteome based technologies are providing new insights into these defects.

"A substantial advance in diabetes care would allow individuals to have euglycaemia without risk of severe hypoglycaemia, and with much less effort than is currently devoted to intensive therapy."

Type 1 Diabetes: new perspectives on disease pathogenesis and treatment. Atkinson A, Esienbarth GS. Lancet 2001: 358:221-29

Nateglinide (Starlix®)

CLINICAL USES OF the MEGLITINIDES STARLIX® (Nateglinide) and PRANDIN® (Repaglinide)

1. Initial therapy. Before Metformin (30% GI side effects with Metformin at indicated doses; rises with dose). May be used with new onset diabetics with blood sugars as high as 500 mg% and with or without a history of ketoacidosis. Remember that Metformin is contraindicated if there is a history of DKA. (For various reasons some patients wish not to use insulin.) Always initiate with a TZD.

2. As adjunctive therapy in patients with moderate to severe beta-cell mass reduction. From one to three times daily with meals. In these patients with normal renal function can be used with Lantus plus one or two injections of short-acting insulin (Humalog or Novolog). It should be used to “separate” the short-acting insulin injections. This will always avoid the hypoglycemia associated with the ADA recommended “Tight Control” method; which is a failed strategy.

3. In patients with moderate to severe renal failure. Since the only route of elimination of any form of insulin is renal; accumulation of insulin is progressive with renal impairment. For GFR’s from 40-60 approx. Regular insulins may persist in circulation for 24 hrs. Below GFR’s of 40 approximately it is safer to use short-acting insulins (Apidra, Humalog or Novolog) with two meals per day, separated by Nateglinide (Starlix®). In advanced renal failure (patients may be on dialysis) initiate therapy with Nateglinide bid to tid.

1. Initial Therapy

Starlix® With TZD

resulting in Remission for over 18 months

NIDDM in RemissionFirst diagnosed with DM 4/2003.

Started on Metformin 500 bid, Glucotrol XL 2.5 mg once in AM.

Developed diarrhea with Metformin. Liver enzyme elevation.

Revised Therapy: Avandia 4 mg and Starlix® 120 mg ac large meals. Switched to Actos 30, then Actos 15 mg. Lipitor 10 mg qd.

Off of DM Rx for 18 months before mild relapse with URI. Remission re-established with 2 weeks of glitazone therapy. Total, (with brief mild relapse)remission: 28 months.

James V. Age 38

4/22/03 Onset of blurred vision and polydipsia RBS in ER 579 mg%6/26/03 Starlix 120 mg bid to tid. Actos 30 mg RBS 107 mg%7/10/03 Actos 15 mg stopped RBS 101 mg%7/17/03 No medication for DM. Lipitor RBS 122 mg%8/14/03 “ RBS 90 mg%9/03/03 “ RBS 82 mg%10/15/03 “ FBS 84 mg%12/02/03 “ FBS 96 mg%12/08/03 “ RBS 135 mg%01/19/04 “ RBS 134 mg%03/01/04 “ RBS 97 mg%04/09/04 “ RBS 107 mg%04/16/04 “ RBS 86 mg%06/28/04 “ RBS 92 mg%08/30/04 “ RBS 97 mg%09/08/04 “ FBS 111 mg%03/19/05 “ RBS 176 mg% URI/ 2 weeks of Actos 45 mg 03/25/06 “ RBS 118 mg%– HgbA1C Date

9.0 4/25/035.5 8/26/035.5 12/02/035.9 4/09/045.9 9/02/04

2. Adjunctive Therapy

when adequate β-cell mass

exists

or

has been restored.

Patient J.D.

4/19/06 . First visit with me. Male. Age 22. DM for 6 years. Highest blood sugar was over 500 mg% He has diabetic neuropathy and nephropathy. (microalbuminuria.) 12/24/04. HgbA1c 9.5

He was treated by another physician with Lantus® 80 units per day and Actos® 30 mg per day.

1/24/06: 9.1 HgbA1c.

4/26/06: Starlix® begun at 120 mg 3 x per day. Actos® 45 mg daily. Lantus® 80 units per day.

5/3/06: Lantus® to 85. Starlix® tid. Actos® 45.

5/10/06. Lantus® to 90 units. Starlix® x tid. Actos® 45.

5/24/06. Lantus® to 85 units.

Patient J.D.

Patient J.D. After Starlix Added

Patient H.B.

70 y.o. woman first seen my me on 9/12/05. S/p partial pneumonectomy forlung cancer. DIABETIC FOR 20 YEARS.

Prior treatment: Metformin 1000 mg bid.  Amaryl 4 mg.  Amytriptilline 50mg daily. Atenolol 50 mg per day.  Dylipidemia: Crestor 10 mg started.10/26/055. Lantus insulin started at 15 units.  Actos 45 mg continued.12/28/05 : Atenolol stopped. Avapro 150 mg started.  Lantus at 20 units. Actos 45 mg.  Starlix 120 mg started at lunch only.1/12/06. Atenolol at 25 mg. Lantus to 25 units.1/26/06: Avapro to 300 mg.

2/2/06. Starlix increased to 3 x/day.   Actos 45 mg. Lantus 25 units.5/15/06: Lantus stopped. Was down to 15 units.5/30/06. Off Lantus. Off Starlix.  On Actos 45 mg.

Patient H.B.

Patient H.B.

Patient M.S.

  Male. Age 44. Peripheral neuropathy and erectile impotence, and

angina. DM for 7 years.

3/23/06. First seen by me Immediately started on Starlix(3/23/06) three times daily. Actos increased to 45 mg per day.   Highestblood sugar over 315.  Lowest sugar occurred in January '06. It was 64mg% when he was on Actos 30 mg, Glipizide and possibly a  HCTZ.

3/24/06 Aic  7.2

4/18/06: Starlix reduced to 120 mg once daily with dinner. 

Erectile impotence has resolved.  LE peripheral neuropathy slightly improved.

Patient M.S.

Patient M.S.

Patient J.O.

45 y.o. male with 3 yr hx of DM.

Starting HgbA1C 11.0 on 4/21/06 Mean plasma glucose 314 mg%.

Started on Starlix 120 mg bid and Actos 45 mg. Advanced to tid. by next visit. Glucophage 500 mg bid added on 4/27/06. Also on Zocor 20 mg daily. Cholesterol/HDL ratio 7.4.

By 6/8/06 he reduced his own Glucophage to 500 mg once in the AM. He has no nocturia. Mean plasma glucose glucose 138 mg %

Patient J.O.

Patient C G

70 y.o. female with DM for over 8 yrs. Meds: Starlix 120 mg tid. Glucophage 850 mg bid. Actos 45 mg daily. HgbA1c 7.3 1/5/05

Patient C.G.

Patient C.G.

Patient F.A.

57 y.o. male DM x 12 yrs 9/29/2000 HgbA1C 9.0 July 7/2/06 HgbA1C 8.2 No DKA in past hx. 7/8/2004: AvandaMet 2/500 bid.

1/3/06. I took over care. Pt. on Glyburide/Metformin combo 5/500 bid.

2/8/06. Metformin 500 mg bid. Starlix 120 mg tid. Actos 45 mg daily. 4/21/06. Metformin 850 mg bid. Actos 45 mg daily. Starlix 120 mg

tid. 5/1/06 Lantus 20 units q AM. Actos 45 mg. Starlix 120 mg tid. 6/6/06 Lantus 15 units. Starlix 120 mg tid. Actos 45 mg daily.

RBS in office afternoon of 7/12/06 84 mg% No low spells.

Patient F.A.

Patient F.A.

Metabolism & Drug Interactions In vitro drug metabolism studies indicate that Starlix is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%).

Starlix is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments.

Glyburide: In a randomized, multiple-dose crossover study, patients with Type 2 diabetes were administered 120 mg Starlix three times a day before meals for 1 day in combination with glyburide 10 mg daily. There were no clinically relevant alterations in the pharmacokinetics of either agent.

Metformin: When Starlix 120 mg three times daily before meals was administered in combination with metformin 500 mg three times daily to patients with Type 2 diabetes, there were no clinically relevant changes in the pharmacokinetics of either agent.

Drug Interactions

Warfarin: When healthy subjects were administered Starlix 120 mg three times daily before meals for four days in combination with a single dose of warfarin 30 mg on day 2, there were no alterations in the pharmacokinetics of either agent. Prothrombin time was not affected.

Diclofenac: Administration of morning and lunch doses of Starlix 120 mg in combination with a single 75-mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent.

Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro .

However, prudent evaluation of individual cases is warranted in the clinical setting. Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, and non-selective beta-adrenergic-blocking agents may potentiate the hypoglycemic action of Starlix and other oral antidiabetic drugs.

Certain drugs including thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce the hypoglycemic action of Starlix and other oral antidiabetic drugs. When these drugs are administered to or withdrawn from patients receiving Starlix, the patient should be observed closely for changes in glycemic control.

Drug/Food Interactions The pharmacokinetics of nateglinide were not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels were significantly reduced when Starlix was administered 10 minutes prior to a liquid meal. Starlix did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.

The End

Las Ramblas Barcelona, Spain August 2005