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Background
This is a group of metabolic disorders all characterized by impaired glucose metabolism. Diabetes should be properly referred to as diabetes mellitus, in distinction from diabetes insipidus. Primary diabetes mellitus has been divided into insulin dependent (type 1) and non-insulin dependent (type 2). Type 2 diabetes can further be divided into nonobese, obese, and maturity-onset diabetes of the young.
It is important to exclude secondary causes of diabetes mellitus which may be curable. Such causes include hemochromatosis, chronic pancreatitis, hormonal tumors, durgs, and some genetic disorders. In addition to helping to establish the initial diagnosis by laboratory analysis, pathologists are more often called upon to evaluate the ravages of the disease upon the end organ systems. Amputations of the lower limbs is a frequent complication and histologic examination often reveals advanced atherosclerotic vascular changes coupled with gangrene. The kidneys may have repeated episodes of infections leading to a non-functioning kidney. Even the skin may show rare changes such as necrobiosis lipoidica diabeticorum, an unusual degenerative change occuring within the dermis.
The classic triad of diabetes is: polyuria, polydipsia, and polyphagia. Increased levels of glucose in the blood leads to hyperosmolarity and depletion of intracellular water. This triggers thirst centers in the brain leading to thirst (polydipsia). Insulin deficiency leads to catabolism of proteins and fat leading to a negative energy balance and increased appetite (polyphagia). Finally, the increased blood glucose spills over into the kidney as well as promoting an osmotic diuresis leading to polyuria. In type 1 patients, one complication of uncontrolled diabetes is ketoacidosis while in type 2 patients, a hyperosmolar nonketotic coma may ensue. See the outline below for more details.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS DM
DiabetesINCIDENCE About 13 million people afflicted in the United States with about half clinically diagnosed
Annual mortality rate of 54,0007th leading cause of death in the United States
Lifetime risk of developing type 2 diabetes for an American adult is 5-7% and for type 1, it is 0.5%
AGE RANGE-MEDIAN 50% >55 years
Type 1 usually onset about 20 years
Type 2 onset about >40 yearsCOFFEE CONSUMPTION
- Coffee consumption and risk of type 2 diabetes: a systematic review.
van Dam RM, Hu FB.
Department of Nutrition and Health, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, the Netherlands.
JAMA. 2005 Jul 6;294(1):97-104 Abstract quote.
CONTEXT: Emerging epidemiological evidence suggests that higher coffee consumption may reduce the risk of type 2 diabetes.
OBJECTIVE: To examine the association between habitual coffee consumption and risk of type 2 diabetes and related outcomes.
DATA SOURCES AND STUDY SELECTION: We searched MEDLINE through January 2005 and examined the reference lists of the retrieved articles. Because this review focuses on studies of habitual coffee consumption and risk of type 2 diabetes, we excluded studies of type 1 diabetes, animal studies, and studies of short-term exposure to coffee or caffeine, leaving 15 epidemiological studies (cohort or cross-sectional).
DATA EXTRACTION: Information on study design, participant characteristics, measurement of coffee consumption and outcomes, adjustment for potential confounders, and estimates of associations was abstracted independently by 2 investigators.
DATA SYNTHESIS: We identified 9 cohort studies of coffee consumption and risk of type 2 diabetes, including 193 473 participants and 8394 incident cases of type 2 diabetes, and calculated summary relative risks (RRs) using a random-effects model. The RR of type 2 diabetes was 0.65 (95% confidence interval [CI], 0.54-0.78) for the highest (>or=6 or >or=7 cups per day) and 0.72 (95% CI, 0.62-0.83) for the second highest (4-6 cups per day) category of coffee consumption compared with the lowest consumption category (0 or <or=2 cups per day). These associations did not differ substantially by sex, obesity, or region (United States and Europe). In the cross-sectional studies conducted in northern Europe, southern Europe, and Japan, higher coffee consumption was consistently associated with a lower prevalence of newly detected hyperglycemia, particularly postprandial hyperglycemia.
CONCLUSIONS: This systematic review supports the hypothesis that habitual coffee consumption is associated with a substantially lower risk of type 2 diabetes. Longer-term intervention studies of coffee consumption and glucose metabolism are warranted to examine the mechanisms underlying the relationship between coffee consumption and type 2 diabetes.
CHARACTERIZATION Radiographs BLOOD FLOW
Division of Dermatology, Department of Medicine, University of Nebraska College of Medicine, 98465 Nebraska Medical Center, Omaha, NE 68132, USA.
BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a granulomatous skin reaction found in < 1% of diabetic patients. Our purpose was to determine if NLD represented areas of cutaneous ischemia.
METHODS: Using laser Doppler flowmetry, we measured cutaneous blood flow in nine diabetic patients at NLD lesions and at contiguous uninvolved sites. Flow values were also determined at several reference sites noncontiguous with the NLD lesions and compared to age- and sex-matched controls: 24 diabetic subjects without skin abnormalities, 18 diabetic patients with dermopathy, and 40 nondiabetic subjects.
RESULTS: NLD lesions exhibited significantly higher blood flow (4.8 +/- 0.7 ml/min/100 g) than areas of unaffected skin close to the lesions (1.2 +/- 0.1 ml/min/100 g) (P < 0.01 for both comparisons). There were no significant differences in flow between normal skin sites in NLD patients and normal sites in diabetic patients without skin lesions.
CONCLUSIONS: Our findings refute the hypothesis that NLD is a manifestation of microvascular ischemic disease of the skin. The increased blood flow seen in NLD lesions suggests an ongoing inflammatory process.
University of Texas MD Anderson Cancer Center, Houston, Tex, USA.
Laboratory Markers American Diabetes Association Guidelines for Diabetes Mellitus (1999)
All criteria require confirmation on a different day than the original abnormal result Screening should be repeated at 3 year intervals if initial screening is negative
First Diagnostic Test Fasting Glucose Recommendations All adults>45 yrs
Younger adults who are obese, family history of diabetes, or with risk factors (high risk ethnic groups, hypertension, low HDL, high TG, impaired fasting glucose) Delivered a baby >9 lbs Non-Pregnant Adults Interpretation Diabetes Diabetes Diabetes Impaired Fasting Glucose OTHER GLYCATED HEMOGLOBIN
Glycated hemoglobin and related factors in diabetic children and adolescents under 18 years of age: a Belgian experience.Dorchy H, Roggemans MP, Willems D.
Diabetology Clinic, University Chiklren's Hospital Queen Fabiola, Brussels, Belgium.
Diabetes Care 1997 Jan;20(1):2-6 Abstract quote OBJECTIVE: To determine, in an unselected population of diabetic children and adolescents < 18 years of age, which HbA1c levels can be achieved, and to examine the relationships with insulin regimen, insulin dose, sex, diabetes duration, BM1, and frequency of home blood glucose monitoring (HBGM) and outpatient clinic attendance.
RESEARCH DESIGN AND METHODS: A total of 144 unselected subjects (73 boys and 71 girls) aged 11.8 +/- 3.7 years (mean +/- SD) were included in the study over a 6-month period. They had diabetes durations ranging from 5 months to 15 years (4.0 +/- 3.0). They were followed by the same pediatric diabetologist and the same nurse. The yearly frequency of visits was 8.9 +/- 2.0, and the monthly frequency of HBGM was 111 +/- 27. Of the patients, 129 were treated with two daily insulin injections of an individualized mixture of rapid- and intermediate-acting insulins, and 15 adolescents were treated with four injections using the basal-bolus regimen. The patients were divided into two subgroups according to diabetes duration: < or = 2 years (n = 53) and > 2 years (n = 91), i.e., outside the honeymoon period. HbA1c was measured by a high-pressure liquid chromatography method (normal values 3.9-5.5%).
RESULTS: The mean +/- SD HbA1c level in the 144 children and adolescents was 6.6 +/- 1.2% using our method. In 62% of the patients, it was possible to obtain an HbA1c level under the normal mean value plus 5 SD. HbA1c was not related to sex, number of insulin injections, or age, i.e., it was not poorer at adolescence. The mean daily insulin dose was 0.9 U/kg body wt, being lower during the first 2 years of diabetes and reaching 1 U at adolescence. HbA1c levels were lower during the first 2 years of diabetes (6.2 +/- 1.0%) than afterwards (6.9 +/- 1.2%), but the frequencies of outpatient visits and HBGM were higher. After 2 years, HbA1c was negatively correlated with the frequency of HBGM. The yearly incidence rate of severe hypoglycemic episodes was 0.2. After the age of 13 years, BM1 was significantly higher in girls and in adolescents on four daily injections.
CONCLUSIONS: In nearly two-thirds of diabetic children and adolescents, it is possible to obtain HbA1c levels under the normal mean plus 5 SD, which is considered satisfactory and close to that of the adult cohort of the Diabetes Control and Complications Trial (DCCT) with intensive treatment. There is no difference between the children on only two daily insulin injections and the adolescents on four injections. After 2 years of diabetes, increased frequency of HBGM helps reduce HbA1c levels, taking into account the "intensive" education of the patients and their families. Adolescent girls on four injections must pay attention to the risk of becoming overweight.
RANDOM BLOOD GLUCOSE LEVELS
Diurnal variation in fasting plasma glucose: implications for diagnosis of diabetes in patients examined in the afternoon.Troisi RJ, Cowie CC, Harris MI.
National Institute of Diabetes and Digestive and Kidney Diseases, Room 695, 6707 Democracy Blvd, MSC-5460, Bethesda, MD 20892, USA.
JAMA 2000 Dec 27;284(24):3157-9 Abstract quote CONTEXT: Current diagnostic criteria for diabetes are based on plasma glucose levels in blood samples obtained in the morning after an overnight fast, with a value of 7.0 mmol/L (126 mg/dL) or more indicating diabetes. However, many patients are seen by their physicians in the afternoon. Because plasma glucose levels are higher in the morning, it is unclear whether these diagnostic criteria can be applied to patients who are tested for diabetes in the afternoon.
OBJECTIVES: To document diurnal variation in fasting plasma glucose levels in adults not known to have diabetes, and to examine the applicability to afternoon-examined patients of the current diagnostic criteria for diabetes.
DESIGN, SETTING, AND PARTICIPANTS: Analysis of data from the US population-based Third National Health and Nutrition Examination Survey (1988-1994) on participants aged 20 years or older who had no previously diagnosed diabetes, who were randomly assigned to morning (n = 6483) or afternoon (n = 6399) examinations, and who fasted prior to blood sampling.
MAIN OUTCOME MEASURES: Fasting plasma glucose levels in morning vs afternoon-examined participants; diabetes diagnostic value for afternoon-examined participants.
RESULTS: The morning and afternoon groups did not differ in age, body mass index, waist-to-hip ratio, physical activity index, glycosylated hemoglobin level, and other factors. Mean (SD) fasting plasma glucose levels were higher in the morning group (5.41 [0.01] mmol/L [97.4 inverted question mark0.3 inverted question mark mg/dL]) than in the afternoon group (5.12 [0.02] mmol/L [92.4 inverted question mark0.4 inverted question mark mg/dL]; P<.001). Consequently, prevalence of afternoon-examined participants with fasting plasma glucose levels of 7.0 mmol/L (126 mg/dL) or greater was half that of participants examined in the morning. The diagnostic fasting plasma glucose value for afternoon-examined participants that resulted in the same prevalence of diabetes found in morning-examined participants was 6.33 mmol/L (114 mg/dL) or greater.
CONCLUSIONS: Our results indicate that if current diabetes diagnostic criteria are applied to patients seen in the afternoon, approximately half of all cases of undiagnosed diabetes in these patients will be missed.
HISTOLOGICAL TYPES CHARACTERIZATION BREAST (DIABETIC MASTOPATHY)
Departments of *Pathology daggerGeneral Surgery, University of Colorado at Denver Health Sciences Center, Denver, CO double daggerDepartment of Pathology, Vanderbilt University Medical Center, Nashville, TN.
We report a case of a 66-year-old woman who presented with multiple painless masses in both breasts. Prior bilateral biopsies were diagnosed as Rosai-Dorfman disease (Sinus Histiocytosis with Massive Lymphadenopathy). A recent lumpectomy specimen revealed a gray-white smooth cut surface with a discrete masslike lesion. The histopathology demonstrated a fibrotic breast parenchyma with foci of dense fibrosis and scattered inconspicuous breast epithelium surrounded by lymphocytes that formed aggregates and follicles with germinal centers. The inflammation was in a periductal, perilobular, and perivascular distribution. In addition, an exuberant inflammatory response with histiocytes and fibroblasts was present. This inflammatory response focally surrounded areas of fat necrosis and formed noncaseating granulomas with rare multinucleated giant cells. This process had infiltrative, ill-defined edges and involved the subcutaneous tissues. The overlying epidermis was normal. The final diagnosis was diabetic mastopathy with an exuberant lymphohistiocytic response.
The differential diagnosis included Rosai-Dorfman disease, inflammatory myofibroblastic tumor, granulomatous mastitis, sclerosing lipogranulomatous response/sclerosing lipogranuloma, lupus panniculitis, and rheumatoid nodules.
Immunohistochemical studies and flow cytometry confirmed the polyclonal nature of the lymphoid infiltrate. After the histologic evaluation, we inquired if the patient had a history of diabetes mellitus, and learned that she did have type 2 noninsulin-dependent diabetes mellitus. In conclusion, we report a case of diabetic mastopathy that presents with bilateral tumorlike masses and an unusual exuberant lymphohistiocytic response with granuloma formation.
The pathologist may not be provided with a history of diabetes mellitus, but the characteristic fibrosis, lymphocytic ductitis/lobulitis, and sclerosing lobulitis with perilobular and perivascular lymphocytic infiltrates should provide clues for an accurate diagnosis, even when an exuberant and an unusual lymphohistiocytic response is present.
A timely accurate diagnosis can help limit repeat surgeries in this vulnerable group of patients.
Lymphocytic mastitis and diabetic mastopathy: a molecular, immunophenotypic, and clinicopathologic evaluation of 11 cases.Valdez R, Thorson J, Finn WG, Schnitzer B, Kleer CG.
Department of Pathology, University of Michigan Medical School (RV, WGF, BS, CGK), Ann Arbor, Michigan.
Mod Pathol 2003 Mar;16(3):223-8 Abstract quote Lymphocytic mastitis and diabetic mastopathy are uncommon fibroinflammatory breast diseases. The lesions seen in these entities are unique in that the associated lymphoid infiltrates are composed of predominantly B cells. In addition, B-cell lymphoepithelial lesions, a finding commonly associated with extranodal marginal zone B-cell/mucosa-associated lymphoid tissue (MALT) lymphomas, are also often present in lymphocytic mastitis and diabetic mastopathy. Although the clinical and immunomorphologic features are well characterized, the clonality of the B-cell infiltrate and the lymphomatous potential of lymphocytic mastitis and diabetic mastopathy have not been emphasized in the literature.
We evaluated 11 cases of lymphocytic mastitis/diabetic mastopathy for immunoglobulin heavy chain gene rearrangement and correlated the findings with all available clinical data. A longstanding history of Type I diabetes mellitus was present in seven patients. One nondiabetic patient had Sjogren's syndrome, and two patients had no history of diabetes mellitus or other autoimmune disease. Clinical data were unavailable for one patient. B-cell-predominant lymphoid infiltrates were seen in all cases, and B-cell lymphoepithelial lesions were found in five. No evidence of a B-cell clone was found in any of the 11 cases by appropriately controlled immunoglobulin heavy chain gene rearrangement studies, and none of the patients developed lymphoma during follow-up intervals ranging from 2-126 months.
These findings suggest that despite the presence of B-cell-predominant lymphoid infiltrates and lymphoepithelial lesions, lymphocytic mastitis and diabetic mastopathy do not appear to be associated with an increased risk for lymphoma.
Glomerular lesions:
Thickening of the glomerular capillary basement membranes
Diffuse glomerulosclerosis with mesangial cell proliferation
Nodular glomerulosclerosis (ball-like deposits with a laminated matrix within a mesangial core of the lobule) with Kimmelstiel-Wilson lesion (capillary loops with halos about the nodule)-found in 10-35% of cases
Renal atherosclerosis and arteriolosclerosis
Pyelonephritis with necrotizing papillitis
- Isolate diffuse thickening of glomerular capillary basement membrane: a renal lesion in prediabetes?
Mac-Moune Lai F, Szeto CC, Choi PC, Ho KK, Tang NL, Chow KM, Li PK, To KF.
1Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
Mod Pathol. 2004 Dec;17(12):1506-12. Abstract quote
A total of 23 patients with proteinuria and isolated ultrastructural diffuse thickening of the glomerular capillary basement membrane were studied, focusing on the possibility of diabetes mellitus, morphometry of the capillary basement membrane, and the comparison with three other groups of patients. These included 14 patients with minimal change nephropathy (MCN), 45 patients with type II diabetes arbitrarily divided into 11 early and 34 late diabetic patients, defined, respectively, as less than 3 and over 5 years history, and 13 patients biopsied for transient mild proteinuria or hematuria, with no evidence of renal disease on follow-up were used as controls.
The level of proteinuria and prevalence of hematuria were similar in patients with isolated thick basement membrane and with diabetes. Diabetic retinopathy was present in 10% of early diabetes, 69% of late diabetes, but not in isolated thick basement membrane. Kimmelstiel-Wilson nodules were seen in late diabetes, and not in other patients. Hyaline arteriosclerosis was more common in late diabetes than in early diabetes or isolated thick basement membrane. The basement membrane thickness was similar between controls (371+/-17 nm) and MCN (345+/-16 nm), between patients with isolated thick basement membrane (482+/-69 nm) and early diabetes (457+/-64 nm), but significantly thicker in isolated thick basement membrane as compared to controls and MCN. In patients with isolated thick basement membrane, the basement membrane thickness was not correlated with age, smoking, body weight, hyaline arteriosclerosis, and hypertension. However, blood tests for diabetes were positive in 20% of patients at biopsy, in 44% at 6 months and 70% at 24 months follow-up, while seven patients showed no evidence of diabetes on follow-up.
Patients with proteinuria and isolated thick glomerular basement membrane must be differentiated from MCN for therapeutic implications, and specifically managed for its strong association with prediabetes or early diabetes.
IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy.
Nasr SH, Markowitz GS, Whelan JD, Albanese JJ, Rosen RM, Fein DA, Kim SS, D'Agati VD.
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Hum Pathol. 2003 Dec;34(12):1235-41 Abstract quote.
Two pathological patterns of acute poststaphylococcal glomerulonephritis are well defined and include (1) an acute proliferative and exudative glomerulonephritis closely resembling classical acute poststreptococcal glomerulonephritis in patients with Staphylococcus aureus infection and (2) a membranoproliferative glomerulonephritis in patients with Staphylococcus epidermidis infection secondary to ventriculovascular shunts.
In this study, we report a novel immunopathologic phenotype of immunoglobulin (Ig) A-dominant acute poststaphylococcal glomerulonephritis occurring in patients with underlying diabetic nephropathy. Five patients with type 2 diabetes presented with acute renal failure occurring after culture-positive staphylococcal infection. Renal biopsy disclosed an atypical pattern of acute endocapillary proliferative and exudative glomerulonephritis with intense deposits of IgA as the sole or dominant immunoglobulin, mimicking IgA nephropathy. The deposits were predominantly mesangial in distribution with few subepithelial humps. All five cases occurred superimposed on well-established diabetic nephropathy. Outcome was poor with irreversible renal failure in four of five (80%) cases.
The possible pathophysiological basis of this atypical form of acute poststaphylococcal glomerulonephritis in diabetic patients is explored. Proper recognition of this entity is needed to avoid an erroneous diagnosis of IgA nephropathy, with corresponding therapeutic and prognostic implications.LIVER
- Glycogenic Hepatopathy: An Underrecognized Hepatic Complication of Diabetes Mellitus.
Torbenson M, Chen YY, Brunt E, Cummings OW, Gottfried M, Jakate S, Liu YC, Yeh MM, Ferrell L.
*Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD daggerDepartment of Pathology, University of California San Francisco, San Francisco, CA double daggerSt. Louis University Liver Center, Department of Pathology, St. Louis University School of Medicine, St. Louis, MO section signDepartment of Pathology, Indiana University School of Medicine, Indianapolis, IN perpendicularDepartment of Pathology, Duke University Medical Center, Durham, NC paragraph signDepartment of Pathology, Rush University Medical Center, Chicago, IL musical sharpDepartment of Pathology, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH **Department of Pathology, University of Washington Medical Center, Seattle, WA.
Am J Surg Pathol. 2006 Apr;30(4):508-513. Abstract quote
Reported are the clinical and pathologic features of glycogenic hepatopathy, a pathologic overloading of hepatocytes with glycogen that is associated with poorly controlled diabetes mellitus.
Fourteen cases were studied by stains, including hematoxylin and eosin, trichrome, periodic acid-Schiff, and periodic acid-Schiff with diastase. Ultrastructural analysis was performed in 2 cases. Medical records were reviewed for clinical presentations, laboratory findings, and clinical outcomes. The individuals ranged from 8 to 25 years of age. All had type I diabetes mellitus with poor glycemic control. The clinical presentations included hepatomegaly, abdominal pain, and elevated transaminases (range, 50-1600 IU/L). The transaminases were dramatically elevated in 3 cases to greater than 10 times the upper limit of normal. All biopsies showed diffusely pale staining hepatocytes on hematoxylin and eosin stains, with excessive glycogen accumulation demonstrated by periodic acid-Schiff stains.
Ultrastructural examination revealed marked glycogen accumulation in the cytoplasm and nuclei. Most cases showed no evidence for fatty liver disease: steatosis was absent in 12 of 14 cases, simple steatosis was seen in 1 of 14 cases, and mild steatohepatitis was present in 1 of 14 cases. Mallory hyaline was absent in all cases, acidophil bodies were only rarely seen, and inflammation was absent or minimally present. Fibrosis was typically absent, with only 2 cases demonstrating focal mild fibrosis. Three patients had adequate follow-up and demonstrated improvement of liver enzyme levels with control of blood glucose.
We conclude that glycogenic hepatopathy can cause hepatomegaly and significant transaminase elevations in individuals with type I diabetes mellitus. The pathology is distinct from steatohepatitis.
- Diabetic hepatosclerosis: diabetic microangiopathy of the liver.
Harrison SA, Brunt EM, Goodman ZD, Di Bisceglie AM.
Liver Center, Department of Medicine, Saint Louis University School of Medicine, St Louis, MO 63110, USA.
Arch Pathol Lab Med. 2006 Jan;130(1):27-32. Abstract quote
CONTEXT: Liver disease associated with diabetes mellitus is common and usually takes the form of simple steatosis or nonalcoholic steatohepatitis. After observing a noncirrhotic form of hepatic sinusoidal fibrosis in patients with long-standing diabetes mellitus who underwent liver biopsy, we set about to characterize this novel entity.
DESIGN AND SETTING: Cases with the hallmark histologic findings were gathered at Saint Louis University School of Medicine and the Armed Forces Institute of Pathology.
PATIENTS: The clinical records were examined in a systematic fashion. Results of light microscopy and prepared immunohistochemical stains were reviewed.
MAIN OUTCOME MEASURES: Clinical findings of patients with the histologic, detailed light microscopic, and immunohistochemical findings on biopsies.
RESULTS: Twelve patients were identified from biopsy findings; all had a history of long-standing diabetes mellitus and a noncirrhotic form of hepatic sinusoidal fibrosis not associated with nonalcoholic steatohepatitis. Most of these patients had a body mass index less than 25 kg/m2 and had substantial evidence of microvascular complications, including retinopathy, nephropathy, and peripheral and autonomic neuropathy. Alkaline phosphatase elevation was common. Liver biopsy specimens showed extensive dense perisinusoidal fibrosis, and immunostaining revealed basement membrane components in a perisinusoidal distribution. Features of nonalcoholic steatohepatitis were not present in the biopsy specimens.
CONCLUSIONS: We propose the term diabetic hepatosclerosis for this entity and suggest that it represents a form of diabetic microangiopathy affecting the liver. Further studies are needed to precisely characterize diabetic hepatosclerosis and to understand mechanisms of pathogenesis and the clinical significanceHistologic Features of the Liver in Insulin Resistance–Associated Iron Overload A Study of 139 Patients
Bruno Turlin, MD, Michel H. Mendler, MD, Romain Moirand, MD, PhD, Dominique Guyader, MD, PhD, Anne Guillygomarc'h, MD, and Yves Deugnier, MD
Am J Clin Pathol 2001;116:263-270 Abstract quote
The aim of the present study was to describe histologic features of the liver in insulin resistance-associated hepatic iron overload (IR-HIO), defined as the association of metabolic disorders and hepatic iron overload.
We included 139 patients in the study on the basis of one or more metabolic disorders and liver iron overload unrelated to usual causes. Liver biopsy specimens were reviewed, and histologic data were compared with those of a previously published, well-defined population with genetic hemochromatosis. Iron overload was characterized by a mixed pattern with iron deposits in hepatocytes and sinusoidal cells. Steatosis was present in 59.7% of patients with inflammation in 32.4% of cases. Periportal fibrosis was found in 67.4% of patients. These patients were older, had higher sinusoidal iron scores, and had a higher prevalence of steatosis and inflammation than patients without fibrosis.
Iron overload in IR-HIO was histologically different from that in genetic hemochromatosis.
Neuropathy, usually a peripheral symmetric neuropathy of the lower extremities affecting both motor and sensory function Retinopathy
Cataracts
GlaucomaReduction in number and size of islets
Leukocytic infiltration of islets (insulitis)
Beta cell degranulation (type 1)
Reduction in islet cell mass (type 2)
Amyloid replacement of islets (type 2)
Increase in number and size of islets (nondiabetic newborns of diabetic mothers)SKIN
- Manifestations of cutaneous diabetic microangiopathy.
Ngo BT, Hayes KD, DiMiao DJ, Srinivasan SK, Huerter CJ, Rendell MS.
Division of Dermatology, Department of Medicine, The University of Nebraska School of Medicine, Omaha, Nebraska 68131, USA.
Am J Clin Dermatol. 2005;6(4):225-37. Abstract quote
The etiologies of a variety of skin conditions associated with diabetes have not been fully explained. One possible etiological factor is diabetic microangiopathy, which is known to affect the eyes and kidneys in patients with diabetes. There are many mechanisms by which diabetes may cause microangiopathy. These include excess sorbitol formation, increased glycation end products, oxidative damage, and protein kinase C overactivity. All of these processes occur in the skin, and the existence of a cutaneous diabetic microangiopathy has been well demonstrated. These microangiopathic changes are associated with abnormalities of skin perfusion. Because the skin plays a thermoregulatory role, there is significant capillary redundancy in normal skin. In diabetic patients, loss of capillaries is associated with a decrease in perfusion reserve. This lost reserve is demonstrable under stressed conditions, such as thermal stimulation. The associated failure of microvascular perfusion to meet the requirements of skin metabolism may result in diverse skin lesions in patients with diabetes.
Many skin conditions peculiar to diabetes are fairly rare. Necrobiosis lipoidica diabeticorum (NLD) and diabetic bullae occur very infrequently as compared with diabetic retinopathy and nephropathy. Conversely, there is a correlation between diabetic microvascular disease and NLD. This correlation also exists with more common skin conditions, such as diabetic dermopathy. This relationship suggests that diabetic microangiopathy may contribute to these conditions even if it is not primarily causal.
Clinically, the major significance of diabetic cutaneous microangiopathy is seen in skin ulceration which is very common and has a major impact on diabetic patients. Many factors contribute to the development of diabetic foot ulcers. Neuropathy, decreased large vessel perfusion, increased susceptibility to infection, and altered biomechanics all play a role, but there is no doubt that inadequate small blood vessel perfusion is a major cause of the inability to heal small wounds that eventually results in ulcer formation.
The accessibility of skin capillaries makes cutaneous diabetic microangiopathy an attractive model for research on the evolution of microvascular disease in diabetic patients.Skin Blood Flow in Diabetic Dermopathy
Greg Wigington, BS ;Binh Ngo, MD ;Marc Rendell, MD
Arch Dermatol. 2004;140:1248-1250. Abstract quote
Background Diabetic dermopathy has been termed the most common cutaneous finding in diabetes, occurring in as many as 40% of diabetic patients older than 50 years. Using laser Doppler technology, we tested the hypothesis that dermopathy lesions represented areas of cutaneous ischemia.Design A survey of cutaneous blood flow in diabetic patients with dermopathy and comparison of values with those in nondiabetic patients.
Setting Outpatient clinic specializing in diabetes.
Patients A consecutive sample of 61 diabetic patients (52 men and 9 women; mean ± SEM age, 58 ± 2 years) with dermopathy had blood flow measurements performed at the sites of dermopathy and at contiguous uninvolved sites. Flow values were also determined at several reference sites and compared with those in 41 nondiabetic control subjects (30 men and 11 women; mean age, 53 ± 3 years).
Results Heat-stimulated blood flow values at the knee, ankle, and toe were about 50% lower for the dermopathy patients than for the nondiabetic controls. Yet, despite their reduced skin blood flow reserve, the dermopathy lesions did not show relative ischemia. At the basal temperature of 35°C, flow was 1.1 ± 0.1 mL /min per 100 g of tissue in apparently normal skin vs 2.2 ± 0.2 at dermopathy sites; at 44°C, flow at the normal sites was 7.9 ± 0.3 mL /min per 100 g of tissue vs 12.9 ± 0.6 at dermopathy sites (P<.01 for both comparisons).
Conclusions Although patients with diabetic dermopathy exhibited reduced skin blood flow compared with nondiabetic volunteers, flow levels were considerably higher at the dermopathy sites than at contiguous uninvolved skin sites. These results refute the hypothesis that diabetic dermopathy represents local ischemia. However, it is still possible that the scarring represented by dermopathy lesions is related to decreased skin perfusion due to diabetes.
Accelerated atherosclerosis
Myocardial infarction
Gangrene of the lower extremities
Hyaline arteriolosclerosis
Diabetic microangiopathy with diffuse thickening of the basement membranes
CHARACTERISTICS
BACKGROUND: The cutaneous lesions of diabetes mellitus (DM) and porphyria cutanea tarda (PCT) exhibit distinctive microvascular changes including basement membrane zone thickening and lamellation, morphologically appearing as hyaline-like alterations of the vessel wall. Immunofluorescence demonstrates homogeneous mantles of immunoglobulin in the microvasculature. The staining intensity is variable and in some cases can closely approximate those immunofluorescent changes seen in photoaged skin.
OBJECTIVE: The purpose of this study was to establish an association between the microvascular changes seen in the skin from patients with DM and PCT and the presence of C5b-9 deposition, potentially defining the C5b-9 assay as an additional diagnostic adjunct.
METHODS: Routine light microscopy and immunofluorescence studies were conducted on skin biopsy specimens from 14 patients with cutaneous manifestations of DM and 17 patients with PCT. The immunofluorescence profile included IgG, IgM, IgA, C3, C3d, C4d, and C5b-9.
RESULTS: Fourteen of 14 DM and 17 of 17 PCT skin biopsy specimens revealed extensive granular and homogeneous vascular deposition of C5b-9; a similar pattern was observed for C3d and C4d. Control specimens from patients without DM and PCT, where C5b-9 was not an expected immunoreactant, were negative. Positive controls were cases of vasculitis, scleroderma, and dermatomyositis without DM and PCT where C5b-9 deposition was expected. C5b-9 deposition was observed and was of lesser magnitude than that encountered in patients with PCT or DM.
LIMITATIONS: We were unable to obtain detailed clinical information on some of the diabetic patients in regards to significant extracutaneous vascular complications. In addition, a correlation between hemoglobin 1 Ac levels and the extent of C5b-9 deposition could not be ascertained as the serum levels for hemoglobin 1 Ac were unknown.
CONCLUSION: Granular and homogeneous deposits of C5b-9 in vessels, along with homogeneous deposits of immunoglobulin within the blood vessels, are characteristic immunofluorescence findings in patients with DM and PCT. In regards to potential mechanisms of C5b-9 deposition, decreased metabolism of C5b-9 due to glycosylation of CD59 in the setting of DM and activation of complement by irradiated porphyrins in PCT are proposed. The extent of C5b-9 deposition suggests that this complex may play a pathogenetic role in the evolution of microvascular injury in patients with DM and PCT.
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors In 5% of cases, death is usually by infection CHRONIC RENAL INSUFFICIENCY
Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus.Kramer HJ, Nguyen QD, Curhan G, Hsu CY.
Departments of Preventive Medicine and Epidemiology and Medicine, Division of Nephrology, Loyola University Medical Center, Maywood, Ill.
JAMA. 2003 Jun 25;289(24):3273-7. Abstract quote CONTEXT: Kidney disease in type 2 diabetes mellitus (DM) is more heterogeneous than in type 1 DM. Reduced glomerular filtration rate (GFR) among individuals with type 2 DM may not always be due to classic diabetic glomerulosclerosis, which is associated with albuminuria and retinopathy.
OBJECTIVE: To determine the prevalence of chronic renal insufficiency (CRI), defined as a GFR less than 60 mL/min per 1.73 m2 body surface area (BSA) in the absence of microalbuminuria or macroalbuminuria and diabetic retinopathy among adults with type 2 DM.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of adults aged 40 years or older with type 2 DM in the Third National Health and Nutrition Examination Survey, a probability sample of the total civilian US noninstitutionalized population conducted from 1988-1994.
MAIN OUTCOME MEASURES: The GFR per 1.73 m2 BSA, calculated with serum creatinine, urea nitrogen, and serum albumin levels using the Modification of Diet in Renal Disease Study prediction equation; albuminuria, assessed using spot urine albumin/creatinine ratio; and presence of retinopathy, determined with fundus photography.
RESULTS: Overall, 13% (sampled n = 171) of adults with type 2 DM (n = 1197) had CRI with a population estimate of 1.1 million. Among these adults with CRI, diabetic retinopathy was noted in 28% (n = 58), while the frequencies of microalbuminuria and macroalbuminuria were 45% (n = 64) and 19% (n = 47), respectively. Retinopathy and albuminuria (microalbuminuria or macroalbuminuria) were both absent in 30% (n = 51) of adults with type 2 DM and CRI. The population estimate of adults with type 2 DM and CRI in the absence of diabetic retinopathy or albuminuria was approximately 0.3 million.
CONCLUSIONS: A substantial burden of CRI among persons with type 2 DM in the United States is likely due to renal parenchymal disease other than classic diabetic glomerulosclerosis. Approaches to screening renal disease in the type 2 DM population should incorporate assessment of GFR in addition to monitoring urine albumin excretion and funduscopic changes to ensure that individuals with type 2 DM and CRI not due to diabetic glomerulosclerosis will receive appropriate intervention.
SURVIVAL Atherosclerotic events are the most common cause of death
Mycoardial infarction is the leading cause of death
Type I patients more likely to die from disease than type II patients
TREATMENT ACARBOSE
Acarbose Treatment and the Risk of Cardiovascular Disease and Hypertension in Patients With Impaired Glucose Tolerance: The STOP-NIDDM Trial.Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M.
Research Centre, Centre Hospitalier de l'Universiteacute.
JAMA. 2003 Jul 23;290(4):486-94. Abstract quote CONTEXT: The worldwide explosive increase in type 2 diabetes mellitus and its cardiovascular morbidity are becoming major health concerns.
OBJECTIVE: To evaluate the effect of decreasing postprandial hyperglycemia with acarbose, an alpha-glucosidase inhibitor, on the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (IGT).
DESIGN, SETTING, AND PARTICIPANTS: International, multicenter double-blind, placebo-controlled, randomized trial, undertaken in hospitals in Canada, Germany, Austria, Norway, Denmark, Sweden, Finland, Israel, and Spain from July 1998 through August 2001. A total of 1429 patients with IGT were randomized with 61 patients (4%) excluded because they did not have IGT or had no postrandomization data, leaving 1368 patients for a modified intent-to-treat analysis. Both men (49%) and women (51%) participated with a mean (SD) age of 54.5 (7.9) years and body mass index of 30.9 (4.2). These patients were followed up for a mean (SD) of 3.3 (1.2) years.
INTERVENTION: Patients with IGT were randomized to receive either placebo (n = 715) or 100 mg of acarbose 3 times a day (n = 714).
MAIN OUTCOME MEASURES: The development of major cardiovascular events (coronary heart disease, cardiovascular death, congestive heart failure, cerebrovascular event, and peripheral vascular disease) and hypertension (>/=140/90 mm Hg).
RESULTS: Three hundred forty-one patients (24%) discontinued their participation prematurely, 211 in the acarbose-treated group and 130 in the placebo group; these patients were also followed up for outcome parameters. Decreasing postprandial hyperglycemia with acarbose was associated with a 49% relative risk reduction in the development of cardiovascular events (hazard ratio [HR], 0.51; 95% confidence interval [CI]; 0.28-0.95; P =.03) and a 2.5% absolute risk reduction. Among cardiovascular events, the major reduction was in the risk of myocardial infarction (HR, 0.09; 95% CI, 0.01-0.72; P =.02). Acarbose was also associated with a 34% relative risk reduction in the incidence of new cases of hypertension (HR, 0.66; 95% CI, 0.49-0.89; P =.006) and a 5.3% absolute risk reduction. Even after adjusting for major risk factors, the reduction in the risk of cardiovascular events (HR, 0.47; 95% CI, 0.24-0.90; P =.02) and hypertension (HR, 0.62; 95% CI, 0.45-0.86; P =.004) associated with acarbose treatment was still statistically significant.
CONCLUSION: This study suggests that treating IGT patients with acarbose is associated with a significant reduction in the risk of cardiovascular disease and hypertension.
BEHAVIOR MODIFICATION
- Treatment of high-risk patients with diabetes: motivation and teaching intervention: a randomized, prospective 8-year follow-up study.
Rachmani R, Slavacheski I, Berla M, Frommer-Shapira R, Ravid M.
Department of Medicine, Sackler School of Medicine, Tel-Aviv University, and Meir Hospital, Kfar-Sava, Israel.
J Am Soc Nephrol. 2005 Mar;16 Suppl 1:S22-6. Abstract quote
The aim of this study was to examine whether motivating patients to gain expertise and closely follow their risk parameters will attenuate the course of microvascular and cardiovascular sequelae of diabetes.
A randomized, prospective study was conducted of 165 patients who had type 2 diabetes, hypertension, and hyperlipidemia and were referred for consultation to a diabetes clinic in an academic hospital. Patients were randomly allocated to standard consultation (SC) or to a patient participation (PP) program. Both groups were followed by their primary care physicians. The mean follow-up was 7.7 yr. The SC group attended eight annual consultations. The PP patients initiated on average one additional consultation per year.
There were 80 cardiovascular events (eight deaths) in the SC group versus 47 events (five deaths) in the PP group (P = 0.001). The relative risk (RR) over 8 yr for a cardiovascular event in the intervention (PP) versus the control (SC) group was 0.65 (95% confidence interval, 0.89 to 0.41). There were 17 and eight cases of stroke in the SC and PP groups, respectively (P = 0.05). RR for stroke was 0.47 (95% confidence interval, 0.85 to 0.32). In the SC group, 14 patients developed overt nephropathy (four ESRD) versus seven (one ESRD) in the PP group (P = 0.05). Throughout the study period, BP, LDL cholesterol, and hemoglobin A1c were significantly lower in the PP than in the SC patients.
Well informed and motivated patients were more successful in obtaining and maintaining good control of their risk factors, resulting in reduced cardiovascular risk and slower progression of microvascular disease.INSULIN ASPART (IAsp)
Glycaemic control in type 1 diabetic patients using optimised insulin aspart or human insulin in a randomised multinational study.Tamas G, Marre M, Astorga R, Dedov I, Jacobsen J, Lindholm A; Insulin Aspart Study Goup.
National Centre for Diabetes Care, 1st Department of Medicine, Diabetes Unit, Semmelweis University, Medical Faculty, Koranyi Sandor utca 2A, H-1083, Budapest, Hungary.
Diabetes Res Clin Pract 2001 Nov;54(2):105-14 Abstract quote Insulin aspart (IAsp), is a rapid-acting analogue of human insulin (HI), for use in the meal related treatment of diabetes mellitus. The degree of glycaemic control achieved by IAsp in comparison with HI after algorithm-driven dose optimisation was tested over 3 months.
The prospective, multicentre, randomised, open-label study with parallel groups was performed in 48 centres in 11 countries and included 423 basal-bolus treated patients with Type 1 diabetes. Main outcome measures were blood glucose control assessed by HbA1c, nine-point self-monitored blood glucose profiles, insulin dose, quality of life, hypoglycaemia and adverse events. An algorithm-driven increase occurred in the dose and number of daily injections of basal insulin, particularly in the IAsp group. After 12 weeks of treatment, HbA1c was significantly lower in IAsp compared to HI treated subjects by 0.17 (95% CI 0.30-0.04) (P<0.05). Comparison of the blood glucose profiles showed lower blood glucose levels with IAsp after breakfast (mean 8.4 vs 10.1 mmol/l; P<0.0001) and dinner (8.2 vs 9.3 mmol/l; P<0.01).
There were no differences between treatments in the incidence of hypoglycaemic episodes or in the adverse event profiles. The WHO Diabetes Treatment Satisfaction Questionnaire score for perceived hyperglycaemia was lower with Iasp (P=0.005), and patients found the insulin aspart treatment more flexible (P=0.022). The current study underlines the need for optimising the basal insulin regimen in order to take full advantage of the pharmacodynamics of IAsp.
INSULIN, BASAL-BOLUS
Optimized basal-bolus therapy using a fixed mixture of 75% lispro and 25% NPL insulin in type 1 diabetes patients: no favorable effects on glycemic control, physiological responses to hypoglycemia, well-being, or treatment satisfaction.Janssen MM, Snoek FJ, Masurel N, Hoogma RP, Deville WL, Popp-Snijders C, Heine RJ.
Research Institute for Endocrinology, Reproduction and Metabolism and the Department of Epidemiology and Biostatistics, Faculty of Medicine, Vrije Universiteit Amsterdam, The Netherlands.
Diabetes Care 2000 May;23(5):629-33 Abstract quote OBJECTIVE: To investigate the effects of a multiple injection regimen with a mixture of 75% lispro and 25% intermediate-acting insulin (lispro high mixture [HM]) before meals on glycemic control, physiological responses to hypoglycemia, well-being, and treatment satisfaction.
RESEARCH DESIGN AND METHODS: We studied 35 type 1 diabetes patients. After an 8- to 10-week lead-in period, patients were randomized to HM or human regular insulin therapy for 12-14 weeks. During the lead-in and treatment periods, HbA1c levels and hypoglycemic frequencies were measured, and patients completed the Well-Being Questionnaire and the Diabetes Treatment Satisfaction Questionnaire. In 19 patients, responses to hypoglycemia were tested during stepped euglycemic-hypoglycemic clamps.
RESULTS: HM treatment improved postprandial glycemia but had no effect on HbA1c, frequency of hypoglycemia, well-being, or treatment satisfaction. During experimental hypoglycemia, HM therapy was associated with a slightly lower total adrenaline response and a higher autonomic symptom threshold (i.e., the autonomic symptom response occurred at a lower blood glucose level) than human regular insulin therapy. We speculate that this effect resulted from an accumulation of insulin during the night.
CONCLUSIONS: Multiple injection therapy with HM rather than human regular insulin before meals does not offer advantages regarding glycemic control, frequency of hypoglycemia, well-being, or treatment satisfaction. In addition, this regimen causes an attenuation of the adrenaline and autonomic symptom responses to hypoglycemia.
Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente-lispro).Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL.
Centre Hospitalier de l'Universite de Montreal CHUM, Department of Medicine, University of Montreal, Quebec, Canada.
Diabetes Care 2001 Apr;24(4):625-30 Abstract quote OBJECTIVE: To evaluate and validate appropriate premeal insulin dose reductions for postprandial exercises of different intensities and durations to minimize the risk of exercise-induced hypoglycemia in type 1 diabetic subjects.
RESEARCH DESIGN AND METHODS: Eight male type 1 diabetic patients on a basal-bolus insulin regimen of ultralente (UL) as basal insulin and lispro (LP) as premeal insulin were tested in a randomized, crossover fashion during postprandial exercise at 25% VO2max for 60 min, 50% VO2max for 30 and 60 min, and 75% VOmax for 30 min starting 90 min after a standardized mixed breakfast (600 kcal, 75 g carbohydrates). Each subject served as his own control and was rested after a full dose of insulin LP (LP 100%) and/or 50% (LP 50%) and/or 25% (LP 25%) of the current dose.
RESULTS: At all intensities, the full premeal insulin dose was associated with an increased risk of hypoglycemia. At 25% VO2max for 60 min, a 50% reduction in the premeal insulin dose resulted in plasma glucose of -0.62 mmol/l compared with baseline at the end of exercise. At 50% VO2max for 30 and 60 min, 50 and 75% reductions of the premeal insulin dose were associated with plasma glucose of -0.39 and +0.49 mmol/l, respectively, at the end of the exercise. At 75% VO2max, a 75% reduction of the premeal insulin dose was required to achieve appropriate postexercise plasma glucose (+0.71 mmol/l). Such reductions in the premeal insulin dose resulted in a 75% decrease in the incidence of exercise-induced hypoglycemia.
CONCLUSIONS In well-controlled type 1 diabetic subjects on intensive insulin therapy with the basal-bolus (UL-LP) insulin regimen, risk of hypoglycemia can be minimized during postprandial exercises of different intensities and different durations by appropriate reduction of premeal insulin LP.
Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente-lispro). Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL.
Centre Hospitalier de l'Universite de Montreal CHUM, Department of Medicine, University of Montreal, Quebec, Canada.
Diabetes Care 2001 Apr;24(4):625-30 Abstract quote
OBJECTIVE: To evaluate and validate appropriate premeal insulin dose reductions for postprandial exercises of different intensities and durations to minimize the risk of exercise-induced hypoglycemia in type 1 diabetic subjects.RESEARCH DESIGN AND METHODS: Eight male type 1 diabetic patients on a basal-bolus insulin regimen of ultralente (UL) as basal insulin and lispro (LP) as premeal insulin were tested in a randomized, crossover fashion during postprandial exercise at 25% VO2max for 60 min, 50% VO2max for 30 and 60 min, and 75% VOmax for 30 min starting 90 min after a standardized mixed breakfast (600 kcal, 75 g carbohydrates). Each subject served as his own control and was rested after a full dose of insulin LP (LP 100%) and/or 50% (LP 50%) and/or 25% (LP 25%) of the current dose.
RESULTS: At all intensities, the full premeal insulin dose was associated with an increased risk of hypoglycemia. At 25% VO2max for 60 min, a 50% reduction in the premeal insulin dose resulted in plasma glucose of -0.62 mmol/l compared with baseline at the end of exercise. At 50% VO2max for 30 and 60 min, 50 and 75% reductions of the premeal insulin dose were associated with plasma glucose of -0.39 and +0.49 mmol/l, respectively, at the end of the exercise. At 75% VO2max, a 75% reduction of the premeal insulin dose was required to achieve appropriate postexercise plasma glucose (+0.71 mmol/l). Such reductions in the premeal insulin dose resulted in a 75% decrease in the incidence of exercise-induced hypoglycemia.
CONCLUSIONS In well-controlled type 1 diabetic subjects on intensive insulin therapy with the basal-bolus (UL-LP) insulin regimen, risk of hypoglycemia can be minimized
INSULIN DETEMIR
Comparison of the soluble basal insulin analog insulin detemir with NPH insulin: a randomized open crossover trial in type 1 diabetic subjects on basal-bolus therapy.Hermansen K, Madsbad S, Perrild H, Kristensen A, Axelsen M.
Department of Endocrinology and Metabolism, Aarhus University Hospital, Denmark.
Diabetes Care 2001 Feb;24(2):296-301 Abstract quote OBJECTIVE: Insulin detemir (NN304) is a soluble basal insulin analog developed to cover basal insulin requirements. This trial aimed to compare the blood glucose-lowering effect of insulin detemir with that of NPH insulin (NPH) and to evaluate the two treatments with regard to intrasubject variation of fasting blood glucose, incidence of hypoglycemia, dose requirements, and safety.
RESEARCH DESIGN AND METHODS: This multicenter open randomized crossover trial in 59 type 1 diabetic subjects comprised a 2-week run-in period on a basal-bolus regimen with NPH insulin once daily, followed by two 6-week periods of optimized basal-bolus therapy with either once-daily insulin detemir or NPH insulin.
RESULTS: The area under the curve, in the time interval 23:00-8:00, derived from 24-h serum glucose profiles, was not statistically significantly different for the two treatment periods (insulin detemir:NPH ratio 89.2:83.5, P = 0.59). The intrasubject variation in fasting blood glucose during the last 4 days of treatment was lower for insulin detemir compared with NPH (P < 0.001). Mean dose requirements of insulin detemir were 2.35 times higher (95% CI 2.22-2.48) compared with NPH. During the last week of treatment, fewer subjects experienced hypoglycemic episodes on insulin detemir (60%) compared with NPH treatment (77%) (P = 0.049).
CONCLUSIONS: Insulin detemir was as effective as NPH in maintaining glycemic control when administered at a higher molar dose. The results indicate that insulin detemir may provide more predictable fasting blood glucose with lower intrasubject variation and reduced risk of hypoglycemia compared with NPH.
INSULIN PUMP
Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. Department of Veterans Affairs Implantable Insulin Pump Study Group.
Saudek CD, Duckworth WC, Giobbie-Hurder A, Henderson WG, Henry RR, Kelley DE, Edelman SV, Zieve FJ, Adler RA, Anderson JW, Anderson RJ, Hamilton BP, Donner TW, Kirkman MS, Morgan NA.
Johns Hopkins University School of Medicine, Baltimore, Md 21205, USA.
JAMA 1996 Oct 23-30;276(16):1322-7 Abstract quote OBJECTIVE: To determine whether implantable insulin pump (IIP) therapy and multiple daily insulin (MDI) injections could equally attain improved blood glucose control, and to compare the 2 treatments with respect to reducing daily blood glucose fluctuations, reducing serious hypoglycemic insulin reactions, and improving patients' quality of life.
DESIGN: Randomized clinical trial.
SETTING: Seven Veterans Affairs medical centers.
PATIENTS: One hundred twenty-one male type II diabetic patients between the ages of 40 and 69 years, receiving at least 1 injection of insulin per day and having hemoglobin A1c (HbA1c) levels of 8% or above.
INTERVENTION: Intensive therapy (IIP or MDI) for 1 year.
MAIN OUTCOME MEASURES: Hemoglobin A1c and blood glucose levels.
RESULTS: Blood glucose levels declined to 7.96+/-1.08 mmol/L (143.4+/-19.5 mg/dL) and 8.30+/-1.52 mmol/L (149.6+/-27.4 mg/dL) (mean +/- SD) for IIP and MDI, respectively (P=.57). Hemoglobin A1c levels improved in both groups (time effect P<.001), to means of 7.54%+/-0.83% (MDI) vs 7.34%+/-0.79% (IIP). IIP reduced blood glucose fluctuations compared with MDI (P<.001), and reduced the incidence of mild clinical hypoglycemia by 68% (P<.001); IIP also eliminated the weight gain associated with MDI therapy and yielded better overall quality-of-life (P=.03) and impact-of-disease subscale scores (P=.05). Adverse events included 25% of subjects with episodes of insulin underdelivery due to microprecipitates of insulin within the pump.
CONCLUSIONS: Intensive insulin therapy with IIP and MDI is effective in controlling non-insulin-dependent diabetes mellitus. IIP has significant advantages in reducing glycemic variability, clinical hypoglycemia, and weight gain, while improving aspects of quality of life.
Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes.Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP.
Hopital de Rangueil, CHU de Toulouse, France.
Diabetes Care 2000 Sep;23(9):1232-5 Abstract quote OBJECTIVE: To compare the efficacy of 2 intensified insulin regimens, continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI), by using the short-acting insulin analog lispro in type 1 diabetic patients.
RESEARCH DESIGN AND METHODS: A total of 41 C-peptide-negative type 1 diabetic patients (age 43.5+/-10.3 years; 21 men and 20 women, BMI 24.0+/-2.4 kg/m2, diabetes duration 20.0+/-11.3 years) on intensified insulin therapy (MDI with regular insulin or lispro, n = 9, CSII with regular insulin, n = 32) were included in an open-label randomized crossover study comparing two 4-month periods of intensified insulin therapy with lispro: one period by MDI and the other by CSII. Blood glucose (BG) was monitored before and after each of the 3 meals each day.
RESULTS: The basal insulin regimen had to be optimized in 75% of the patients during the MDI period (mean number of NPH injections per day = 2.65). HbA1c values were lower when lispro was used in CSII than in MDI (7.89+/-0.77 vs. 8.24+/-0.77%, P<0.001). BG levels were lower with CSII (165+/-27 vs. 175+/-33 mg/dl, P<0.05). The SD of all the BG values (73+/-15 vs. 82+/-18 mg/dl, P<0.01) was lower with CSII. The frequency of hypoglycemic events, defined as BG levels <60 mg/dl, did not differ significantly between the 2 modalities (CSII 3.9+/-4.2 per 14 days vs. MDI 4.3+/-3.9 per 14 days). Mean insulin doses were significantly lower with CSII than with MDI (38.5+/-9.8 vs. 47.3+/-14.9 U/day. respectively, P< 0.0001).
CONCLUSIONS: When used with external pumps versus MDI, lispro provides better glycemic control and stability with much lower doses of insulin and does not increase the frequency of hypoglycemic episodes.
A randomized study comparing blood glucose control and risk of severe hypoglycemia achieved by non-programmable versus programmable external insulin pumps.Catargi B, Breilh D, Gin H, Rigalleau V, Saux MC, Roger P, Tabarin A.
University Hospital of Bordeaux, Hopital Haut-Leveque, 33604 Pessac, France.
Diabetes Metab 2001 Jun;27(3):323-7 Abstract quote OBJECTIVE: To compare a non-programmable and a programmable insulin external pump using regular insulin on glycemic stability, the risk of severe hypoglycemia and metabolic control in type 1 diabetic patients.
MATERIAL AND METHODS: Ten type 1 diabetic patients were involved in a randomized, crossover study comparing two periods of 3 months with continuous subcutaneous insulin infusion (CSII) either with a non-programmable insulin pump or a programmable insulin pump. Comparisons were made among mean blood glucose values before and after meals, at bedtime and at 2: 00 a.m.; the risk of severe hypoglycemia assessed by the low blood glucose index (LBGI); and HbA1c.
RESULTS: Mean average blood glucose (BG) measurements were significantly lower with the programmable in comparison with the non-programmable insulin pump (respectively 157+/-78 vs. 165+/-79, p=0.034). While postprandial values for BG were not different between the two pumps, the use of the programmable pump resulted in a significant decrease in mean preprandial BG levels (140+/-68 vs. 150+/-73 mg/dl p=0.039). Conversely mean BG level was lower at 2 a.m. with the non-prgrammable pump (125+/-81 vs. 134 +/-93 mg/dl, p=0.02) but with a higher incidence of hypoglycemia. Mean LBGI was comparable with the two pumps (3.1+/-8.6 vs. 2.8+/-6.9, p=0.1). There was a 0.2% decrease in HbA1c during the programmable pump period that did not reach statistical significance (p=0.37).
CONCLUSIONS: The present study suggests that programmable external insulin pumps, although more complex and more expensive than non-programmable insulin pumps, significantly reduce fasting glycemia during the day without increasing the risk of severe hypoglycemia and are safer during the night.
Comparison of antigenicity of Hoechst 21PH insulin using either implantable intraperitoneal pump or subcutaneous external pump infusion in type 1 diabetic patients.Jeandidier N, Boullu S, Busch-Brafin MS, Chabrier G, Sapin R, Gasser F, Pinget M.
Department of Endocrinology and Diabetes, University Hospital, Strasbourg, France.
Diabetes Care 2002 Jan;25(1):84-8 Abstract quote OBJECTIVE: To assess the antigenicity of the insulin Hoechst 21PH (Hoe21PH) using continuous subcutaneous insulin infusion (CSII) and to compare the antigenicity of this insulin when administered intraperitoneally or subcutaneously.
RESEARCH DESIGN AND METHODS; Peritoneal administration of Hoe21PH (Hoechst-Roussel, Somerville, NJ) insulin using implantable devices (continuous peritoneal insulin infusion [CPII]) increases anti-insulin antibody (AIA) levels in type 1 diabetic patients. Intraperitoneal administration, addition of a stabilizer (polyethylene polypropylene glycol), or insulin modifications due to storage in the pump may be involved in this antigenicity. In this nonrandomized study, 24 type 1 diabetic patients were treated with either CSII (n = 11, group 1) or CPII (n = 13, group 2). AIA levels were measured by radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA) before starting patients on Hoe21PH and again after 3 and 6 months.
RESULTS: Patients were comparable in the two groups. AIA levels (RIA) remained stable (24.3 +/- 8.5% [month 0] to 24.9 +/- 8.5.5% [month 6]) in group 1 and increased (21.8 +/- 6.7% [month 0] to 41.8 +/- 6.9% [month 6]) in group 2 (P = 0.005, Wilcoxon's rank-sum test). Using ELISA, AIA remained stable in the patients in group 1 (n = 9; 3.8 +/- 0.8 units/ml [month 0] and 4.1 +/- 1.0 units/ml [month 6]) and tended to increase in the patients in group 2 (n = 12; 4.1 +/- 0.7 units/ml [month 0] to 17.5 +/- 4.6 units/ml [month 6]) (P = 0.07). Comparison of the evolution of AIA formation between the two groups, using RIA at months 0, 3, and 6 showed a significant difference (analysis of variance, P = 0.009).
CONCLUSIONS: No increase in AIA levels was demonstrated when Hoe21PH insulin was administered subcutaneously as assessed by two different assays. CPII is proven to be more antigenic than CSII, and this is not related to a specific antigenicity of Hoe21PH insulin. The intraperitoneal route of administration or insulin modifications due to insulin storage in implantable devices might explain this antigenicity.
Transition from multiple daily injections to continuous subcutaneous insulin infusion in type 1 diabetes mellitus.Conrad SC, McGrath MT, Gitelman SE.
University of California, San Francisco 94143, USA.
J Pediatr 2002 Feb;140(2):235-40 Abstract quote OBJECTIVE: To review our experience with insulin dosing during the conversion from multiple daily injections to continuous subcutaneous insulin infusion (CSII) for children and adolescents with type 1 diabetes mellitus.
STUDY DESIGN: The charts of 65 children who started CSII from January 1998 to April 2000 were reviewed. Data regarding insulin dose and hemoglobin A1c levels were collected from the prepump visit and first (at 1 to 2 months) and second (at 3 to 6 months) visits after being placed on pump therapy.
RESULTS: Pubertal patients had a decrease in total insulin dose taking CSII; prepubertal patients had little change (-18 +/- 3.5% vs -1.7 +/- 5%, P =.01). On CSII, the basal insulin dose comprised 40% to 45% of total insulin in both prepubertal and pubertal patients. Maximal basal rate in prepubertal patients occurred from 9 PM to 12 AM and in pubertal patients from 3 AM to 9 AM and from 9 PM to 12 AM.
CONCLUSION: Guidelines established for CSII dosing in adults do not necessarily apply to children. The total daily insulin dose needs to be decreased in pubertal patients but may remain unchanged in prepubertal patients. The basal rate comprises 40% to 45% of the total daily insulin dose, and the timing of maximum basal rates is likely to occur in the late evening hours in prepubertal children.
LIVER TRANSPLANTATION Outcome of liver transplantation in patients with diabetes mellitus: A case-control study.
John PR, Thuluvath PJ.
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD.
Hepatology 2001 Nov;34(5):889-95 Abstract quote
The influence of preexisting diabetes mellitus (DM) on outcome after orthotopic liver transplantation (OLT) has not been well defined.
The objective of our study was to compare the morbidity and mortality after OLT in 57 patients with preexisting DM (3 type I, 54 type II) with 114 age-, sex-, and race-matched patients without DM (case controls). The demographics were similar in both groups. Pretransplantation serum creatinine was significantly higher in the diabetic group compared with case controls. The incidence of the following complications was significantly higher in the diabetic group after OLT: cardiovascular (61.4% vs. 21.9%, P <.001), major (54.4% vs. 29.8%, P =.002) and minor infections (29.8% vs. 7.9%, P <.0001), renal (59.7% vs. 20.2%, P <.001), ophthalmologic (10.5% vs. 0.9%, P =.01), respiratory (24.6% vs. 7.0%, P =.001), neurologic (31.6% vs. 7.0%, P <.001), hematologic (19.3% vss 2.6%, P =.001), musculoskeletal (24.6% vs. 5.3%, P =.001), and malignancy (22.8% vs. 10.5%, P =.03). The duration of hospital stay, cost of hospitalization, retransplantation, and overall graft survival were similar. Acute rejection was seen in 50.9% of diabetics compared with 25.4% in controls (P =.0009). One-year (87% vs. 77%) and 2-year (81.6% vs. 70.1%) patient survival was similar, but 5-year survival was lower in the DM group (34.4% vs. 67.7%, P =.002).
In conclusion, preexisting diabetes is associated with a significant post-OLT morbidity and mortality, and our observations suggest that patients with DM warrant more rigorous pre- and post-OLT evaluation.
PENTOXYFYLLINE
Intermittent claudication in diabetics: treatment with exercise and pentoxifylline--a 6-month, controlled, randomized trial.Belcaro G, Nicolaides AN, Griffin M, De Sanctis MT, Cesarone MR, Incandela L, Ippolito E, Pomante P, Geroulakos G, Ramaswami G.
Department of Biomedical Sciences, Chieti University and San Valentino Vascular Screening Project, Pe, Italy.
Angiology 2002 Jan-Feb;53 Suppl 1:S39-43 Abstract quote The aims of this study were to evaluate the effect of PXF (1600 mg daily) in diabetic patients with intermittent claudication.
Of the 60 included patients, 53 completed the study (27 in the PXF group). There were seven dropouts. The groups were comparable for age, sex distribution, and total walking distance (TWD), and risk factors. There was an increase in TWD at 3 and 6 months in both groups (p<0.05) possibly due to exercise. However the increase (both absolute and percentage) in TWD was significantly larger in the PXF group. At 6 months, PXF produced a 292% increase in TWD (vs 180% produced by placebo) (p<0.02). The excess increase produced by PXF treatment was 112% at 6 months in comparison with placebo (p<0.02).
Treatment was well tolerated. Between-group analysis favors PXF considering TWD, and results indicate good efficacy and tolerability.
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Hyaline arteriolosclerosis-Characteristic vascular lesion associated with hypertension. This histologic change is often found in the smaller arterioles in organs such as the kidney.
Insulitis-Histologic finding of a heavy lymphocytic infiltrate around the islets of Langerhans within the pancreas. This is most frequently found in younger diabetics.
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