Mechanism of insulin release in normal pancreatic beta cells (i.e., glucose dependence). Insulin production does not depend on blood glucose levels; insulin is stored pending release
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Diabetes mellitus

Diabetes mellitus is a medical disorder characterized by varying or persistent hyperglycemia (elevated blood sugar levels), especially after eating. All types of diabetes mellitus share similar symptoms and complications at advanced stages. Hyperglycemia itself can lead to dehydration and ketoacidosis. Longer-term complications include cardiovascular disease (doubled risk), chronic renal failure (it is the main cause for dialysis), retinal damage which can lead to blindness, nerve damage which can lead to erectile dysfunction (impotence), gangrene with risk of amputation of toes, feet, and even legs. more...

Dandy-Walker syndrome
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Diabetes mellitus
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The more serious complications are more common in people who have a difficult time controlling their blood sugars with medications (glycemic control).

The most important forms of diabetes are due to decreased or the complete absence of the production of insulin (type 1 diabetes), or decreased sensitivity of body tissues to insulin (type 2 diabetes, the more common form). The former requires insulin injections for survival; the latter is generally managed with diet, weight reduction and exercise in about 20% of cases, though the majority require these strategies plus oral medication (insulin is used if the tablets are ineffective).

Patient understanding and participation is vital as blood glucose levels change continuously. Treatments which return the blood sugar to normal levels can reduce or prevent development of the complications of diabetes. Other health problems that accelerate the damaging effects of diabetes are smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.


Although diabetes has been recognized since antiquity, and treatments were known since the Middle Ages, the elucidation of the pathogenesis of diabetes occurred mainly in the 20th century6.

Until 1921, when insulin was first discovered and made clinically available, a clinical diagnosis of what we now call type 1 diabetes was an invariable death sentence, more or less quickly. Non-progressing type 2 diabetics almost certainly often went undiagnosed then; many still do.

The discovery of the role of the pancreas in diabetes is generally credited to Joseph Von Mering and Oskar Minkowski, two European researchers who, in 1889, found that when they completely removed the pancreas of dogs, the dogs developed all the signs and symptoms of diabetes and died shortly afterward. In 1910, Sir Edward Albert Sharpey-Schafer of Edinburgh in Scotland suggested diabetics were deficient in a single chemical that was normally produced by the pancreas - he proposed calling this substance insulin.

The endocrine role of the pancreas in metabolism, and indeed the existence of insulin, was not fully clarified until 1921, when Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski but went a step further and managed to show that they could reverse the induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs7. They went on to isolate the hormone insulin from bovine pancreases at the University of Toronto in Canada.

This led to the availability of an effective treatment - insulin injections - and the first clinical patient was treated in 1922. For this, Banting et al received the Nobel Prize in Physiology or Medicine in 1923. The two researchers made the patent available and did not attempt to control commercial production. Insulin production and therapy rapidly spread around the world, largely as a result of their decision.


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Increased prevalence of third-degree atrioventricular block in patients with type II diabetes mellitus
From CHEST, 10/1/05 by Mohammad-Reza Movahed

Background: Diabetes mellitus (DM) is a major risk for cardiovascular disease and mortality. There is some evidence that third-degree atrioventricular (AV) block occurs more commonly in patients with DM. In this study, we evaluated any possible association between DM and third-degree AV block using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in a very large inpatient database.

Method: We used patient treatment files containing discharge diagnoses using ICD-9 codes of inpatient treatment from all Veterans Health Administration hospitals. The cohort was stratified using the ICD-9-CM code for DM (n = 293,124), a control group with hypertension butno DM (n = 552,623), and the ICD-9 code for third-degree AV block (426.0) and smoking (305.1, V15.82). We performed multivariate analysis adjusting for coronary artery disease, congestive heart failure, smoking, and hyperlipidemia. Continuous and binary variables were analyzed using [chi square] and Fisher exact tests.

Results: Third-degree AV block diagnosis was present in 3,240 of DM patients (1.1%) vs 3,367 patients (0.6%) in the control group. Using multivariate analysis, DM remained strongly associated with third-degree AV block (odds ratio, 3.1; 95% confidential interval, 3.0 to 3.3; p < 0.0001).

Conclusion: Third-degree AV block occurs significantly more in patients with DM. This finding may, in part, explain the high cardiovasctdar mortality in DM patients.

Key words: arrhythmias; atrioventricular block; diabetes mellitus; third-degree atrioventricular block; conduction abnormalities

Abbreviations: AV = atrioventricular; DM = diabetes mellitus; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; PTF = patient treatment file


Diabetes mellitus (DM) is one of the most chronic conditions worldwide, with an increasing prevalence of approximately 140 million persons having DM. This number is projected to increase to 300 million by the year 2025. (1) The prevalence of cardiovascular disease, such as congestive heart failure and coronary artery disease, is higher in patients with DM, (2-5) and they are at greater risk of death. (6,7) High mortality in patients with DM is independent of other known risk factors for cardiovascular disease (8) and is, in part, contributed to atherosclerotic cardiovascular disease. (7-9) There are reports (10-12) in the literature about increased prevalence of cardiac conduction abnormalities and autonomic neuropathy in patients with DM. In several case reports and small studies, (13-15) third-degree atrioventricular (AV) block is reported in patients with DM. However, most of these studies involves smaller populations. Using a large database, we conducted a retrospective study for the prevalence of third-degree AV block in patients with DM with comparison to a control group. We performed univariate and multivariate analysis adjusting for congestive heart failure, coronary artery disease, and smoking.


Data Collection and Data Sources

The Austin Automation Center has kept patient treatment files (PTFs) since July 1969. The PTF documents inpatient treatment from all Veterans Health Administration hospitals, extended care discharges and non-Veterans Affairs hospital discharges at the Veterans Health Administration expense. The PTF contains demographics of patients and the discharge diagnosis. Since 1984, a primary diagnosis and up to nine secondary diagnoses have been recorded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). (1) This study was approved by Institutional Review Board.

Identification of Cases and Control Subjects

Cases consisted of patients diagnosed with type II DM but free of hypertension. Cases with ICD-9-CM code 250.0 (1) were identified from the PTF for 1990 to 2000. The date of a patient's first appearance in the PTF with type II DM was considered to be the date of diagnosis. Nonmatched control patients without DM were selected from the same patient treatment files during the same period. In order to have a large comparative population as control, we used hypertension as one of the most common diseases in humans. Using hypertension enabled us to have a control population that was larger than the DM population. Nonmatched controls were patients with hypertension (ICD-9-CM codes 401.0, 401.1, and 401.9) but no DM. A total of 845,748 patients were identified. There were 293,124 patients with DM and 552,624 patients in the control group.

Calculation of Comorbidity Index

A comorbidity index was calculated for cases and controls. An adaptation of the Charlson comorbidity index as applied to administrative databases was used. (16,17)

Collected Information and Extraction of Secondary Diagnoses

Demographics were obtained from the computerized records for both cases and controls. Individual social security numbers were used to search the inpatient files (1990-2000) for the following codes: third-degree AV block (426.0), congestive heart failure (428.0), coronary artery disease (414.9), smoking (305.1,V15.82), and hyperlipidemia (272.0-272.4 and 272.09).

Statistical Analysis

The statistical analysis was performed (SAS/STAT; SAS Institute; Cary, NC). Any p value < 0.05 was used as a statistical significance. Continuous variables were calculated by unpaired t tests. Binary variables were studied using [chi square] and Fisher exact tests. Quantitative variables were documented as mean [+ or -] SD. In the multivariate analysis, a logistic regression model was used to calculate the odds of third-degree AV block in patients with DM vs control patients while adjusting for age, gender, and comorbid conditions. Odds ratios and 95% confidence intervals were used to document the strength of influence.


We evaluated 293,124 patients with DM and 552,624 control patients with hypertension but no DM who were hospitalized from 1990 to 2000. The mean age for DM patients and control patients was 65.8 [+ or -] 11.3 years and 64.8 [+ or -] 12.6 years ([+ or -] SD), respectively (p = not significant). Gender (male gender: 97.8% in the DM group and 97.4% in control group) or race (white race: 65.3% in the DM group and 68.3% in control group) were not significantly different in both groups. DM was found to be significantly associated with third-degree AV block in univariate and multivariate analysis. Third-degree AV block diagnosis was present in 3,240 of DM patients (1.1%) vs 3,367 patients (0.6%) in the control group (p < 0.0001). Using multivariate analysis, DM remained significantly associated with third-degree AV block (odds ratio, 3.1; 95% confidence interval, 3.0 to 3.3; p < 0.0001).


This study is the first large-scale study demonstrating that DM is strongly associated with third-degree AV block. Using multivariate analysis, this association is independent of coronary artery disease or congestive heart failure. The cause of this association is not known but is most likely multifactorial. Autonomic neuropathy and metabolic derangement such as hyperkalemia (18) or acidosis (13,14) may explain this association. The occurrence of autonomic neuropathy affecting both sympathetic and parasympathetic neurons in patients with DM is well established (11,19-21) and is thought to be responsible for abnormal higher mean heart rate, (12) arrhythmias, (21) and death. (9) However, there are no studies available examining any association between autonomic neuropathy and conduction abnormalities. Patients with DM have been found to have an increased prevalence of conduction abnormalities such as left bundle-branch block, (22) right bundle-branch block, (23) and bifascicular block. (24) Left bundle-branch block has been found to be related to advance cardiovascular disease (23,25) and sudden death (26) in a general population. The prevalence of patients with DM is significantly higher in patients who require permanent pacemaker treatment, suggesting the susceptibility of these patients to significant bradyarrhythmias. (27) Bundle-branch blocks in patients with DM could progress to higher-degree AV block, explaining our finding, but the evidence for this concept is lacking. However, there are many reports (13,14,18) about the increased prevalence of high-degree AV blocks in patients with DM. Third-degree and high-degree AV blocks have been reported in DM cases during metabolic derangement and with postprandial stress. (28) Furthermore, the prevalence of DM with high-degree AV block has been found to be higher in patients requiring pacemaker treatment (29) and in patients with chronic heart block, (10) consistent with our finding. An autopsy report (30) in a small number of patients with DM and chronic heart block have shown changes in the conduction system typical for DM, such as diabetes microangiopathy. This explains the possible mechanism of this association and the increase risk of sudden death in DM patients. (9,31)


This is a retrospective study, which presents limits. The results are limited to inpatient admissions, and therefore needs to be cautiously applied to an entire population. Our control patients consisted of hypertensive, nondiabetic patients who are not representative of all nondiabetic patients. However, hypertension increases cardiovascular risk; therefore, this association is valid. We had no data about the duration of DM. This study consisted mostly of men in a Veterans Affairs population that limits these data to male patients. We used an administrative database and not clinical data directly from a physician. ICD-9-CM coding is usually done by administrative personnel based on chart reviews and not directly on the patient and, therefore, making the data less accurate and thus limiting our study.


Diabetes mellitus is independently associated with third-degree AV block. This association may, in part, explain the higher risk of sudden death in patients with DM. Our finding is supported by current literature reporting susceptibility of patients with DM for autonomic neuropathy, cardiac conduction abnormalities, and bradyarrhythmias. Furthermore, bundle-branch blocks and high-degree and third-degree AV blocks have been found in patients who require pacemaker treatment. We suggest that more attention should be given to the early detection of life-threatening conduction abnormalities in patients with DM that could potentially decrease the incidence of sudden death in this population.

Manuscript received March 10, 2005; revision accepted May 19, 2005.


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(9) Suarez GA, Clark VM, Norell JE, et al. Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study. J Neurol Neurosurg Psychiatry 2005; 76: 240-245

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(15) Kawai S, Fu L, Aziki K, et al. A degenerative lesion of the approach to the atrioventricular node producing second-degree and third-degree atrioventricular block. Pacing Clin Electrophysiol 1992; 15:2263-2269

(16) Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992; 45:613-619

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(20) Schnell O, Hammer K, Muhr-Becker D, et al. Cardiac sympathetic dysinnervation in type 2 diabetes mellitus with and without ECG-based cardiac autonomic neuropathy. J Diabetes Complicat 2002; 16:220-227

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(27) Grimm W, Langenfeld H, Maisch B, et al. Symptoms, cardiovascular risk profile and spontaneous ECG in paced patients: a five-year follow-up study. Pacing Clin Electrophysiol 1990; 13:2086-2090

(28) Okamoto M, Hashimoto M, Yamada T, et al. Postprandial atrioventricular block in a patient with diabetes mellitus. Intern Med 1997; 36:579-581

(29) Podlaha R, Falk A. The prevalence of diabetes mellitus and other risk factors of atherosclerosis in bradycardia requiring pacemaker treatment. Horm Metab Res Suppl 1992; 26: 84-87

(30) Panja M, Dutta AL, Kar AK, et al. Cardiac changes implicated in chronic heart block. J Assoc Phys India 1991; 39:698-701

(31) El-Atat FA, McFarlane SI, Sowers JR, et al. Sudden cardiac death in patients with diabetes. Curr Diab Rep 2004; 4:187-193

Mohammad-Reza Movahed, MD, PhD; Mehrtash Hashemzadeh, MS; and M. Mazen Jamal, MD, MPH

* From the Division of Cardiology (Dr. Movahed), University of California, Irvine, Medical Center, Orange; and Long Beach Veteran Administration Medical Center (Mr. Hashemzadeh and Dr. Jamal), Long Beach, CA.

Correspondence to: M. Reza Movahed MD PhD FCCP Assistant Clinical Professor, University of California Irvine Medical Center, Department of Medicine, Division of Cardiology, 101 The City Dr, Bldg 53, Rm 100, Orange, CA 92868-4080; e-mail:

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