Vasopressin secretion in the DIDMOAD (Wolfram) syndrome

The diabetes insipidus which accompanies the DIDMOAD (Wolfram) syndrome is thought to be hypothalamic in origin, though no formal study of vasopressin secretion in the syndrome has been published, and some data in the literature suggest a renal tubular defect. We have studied vasopressin secretion in seven patients with the Wolfram/DIDMOAD syndrome during three dynamic stimuli: an osmotic stimulus (hypertonic saline infusion), hypoglycaemia (insulin tolerance test) and a baroregulatory stimulus (trimetaphan infusion). Hypertonic saline infusion demonstrated three patients to have complete and four to have partial hypothalamic diabetes insipidus; administration of (per nasal) desmopressin excluded nephrogenic diabetes insipidus in all seven patients. Insulin hypoglycaemia failed to stimulate vasopressin release, but trimetaphan-induced hypotension produced significant though subnormal rises in plasma vasopressin in three patients with partial diabetes insipidus, though it produced a negligible rise and no rise in plasma vasopressin in two patients with complete diabetes insipidus. The data suggest a much greater frequency of hypothalamic diabetes insipidus in the Wolfram/DIDMOAD syndrome than is reported, but did not identify nephrogenic diabetes insipidus. The absence of vasopressin responses to non-osmotic stimuli in patients with complete diabetes insipidus suggests global lack of vasopressin secreting neurones, rather than an isolated osmoreceptor defect or selective vasopressin secreting neuronal loss, as the lesion producing diabetes insipidus in the DIDMOAD syndrome.     

Vasopressin Secretion in the DIDMOAD (Wolfram) Syndrome

SUMMARY The diabetes insipidus which accompanies the DIDMOAD (Wolfram)Syndrome is thought to be hypothalamic in origin, though noformal study of vasopressin secretion in the syndrome has beenpublished, and some data in the literature suggest arenal tubulardefect. We have studied vasopressin secretion in seven patientswith the Wolfram /DIDMOAD syndrome during three dymatic stimuli:an Osmotic Stimulus (hypertonic Saline infusion), hypoglycaemia(insulin tolerance test) and a baroregulatory stimulus (trimetaphaninfusuion). Hypertonic saline infusion demonstrated three patientsto have complete and four to have partial hypothalamic diabetesinsipidus; administration of (per nasal) desmopressin excludednephrogenic diabetes insipidus in all seven patients. Insulinhypoglycaemia failed to stimulate vasopressin release, but trimetaphan-inducedhypotension produced significant though subnormal rises in plasmavasopressin in three patients with partial diabetes insipidus,though it produced a negligible rise and no rise in plasma vasopressinin two patients with complete diabetes insipidus. The data suggest a much greater frequency of hypothalamic diabetesinsipidus in the Wolfram/DIDMOAD syndrome than is reported,but did not identify nephrogenic diabetes insipidus. The absenceof vasopressin responses to non-osmotic stimuli in patientswith complete diabetes insipidus suggests global lack of vasopressinsecreting neurones, rather than an isolated osmoreceptor defector selective vasopressin secreting neuronal loss, as the lesionproducing diabetes insipidus in the DIDMOND syndr     

Latent Autoimmune Diabetes of Adults (LADA) Is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes

Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes–associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test—islet autoantibody measurement—with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes.     

Insulin glargine (Lantus)

Insulin glargine (Lantus) is a long-acting, human insulin analogue that has been specifically designed to overcome the deficiencies of traditionally available 'intermediate-acting' insulins that are currently used for basal insulin supplementation. In contrast to NPH insulin, subcutaneous insulin glargine injected once daily provides a relatively constant basal level of circulating insulin with no pronounced peak. In patients with type 1 and type 2 diabetes, once-daily insulin glargine achieves equivalent glycaemic control to NPH insulin given once or twice daily In patients with type 1 diabetes, it is associated with significantly lower fasting blood glucose (FBG) levels, especially in those patients previously on twice-daily NPH insulin. Insulin glargine is well tolerated and elicits less hypoglycaemia, especially nocturnal episodes, than NPH insulin, with similar levels of glycaemic control. This benefit is seen in patients with both type 1 and type 2 diabetes, in particular those previously on a once-daily NPH insulin regimen. Patients with type 1 and type 2 diabetes have also reported higher levels of treatment satisfaction when treated with insulin glargine. Insulin glargine provides the opportunity to achieve target blood glucose levels more effectively and safely compared with NPH insulin, due to the reduced risk of hypoglycaemia, especially nocturnal hypoglycaemia. Insulin treatment needs to be individualised, with the dose of insulin glargine adjusted according to the blood glucose level as part of an aggressive regimen in an attempt to achieve near normoglycaemia without incurring episodes of hypoglycaemia. Insulin glargine should be used in combination with short-acting insulin analogues in patients with type 1 diabetes. In patients where oral hypoglycaemic agents are failing, insulin glargine can be added. The early introduction of insulin in patients with type 2 diabetes is to be encouraged.     

Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non-autoimmune (type 2) diabetes

OBJECTIVE: To investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non-autoimmune (type 2) diabetes in young adults. MATERIAL AND METHODS: Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15-34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody-negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3-4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. RESULTS: Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2-3-fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01-0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut-off, the sensitivity and specificity for differentiation between autoimmune and non-autoimmune diabetes were 87% and 92%, respectively. At 3-4 months after clinical onset of diabetes, proinsulin secretion was still 2-3 times higher in type 2 than in type 1 diabetes patients (p<0.001). CONCLUSIONS: Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non-autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.     

Reliability and validity of the Icelandic version of the Problem Area in Diabetes (PAID) Scale

BACKGROUND: Diabetes is a burdensome disease that increases distress among people with diabetes. OBJECTIVES: To test the validity and reliability of an Icelandic version of the problem area in diabetes scale (PAID) and to assess the hitherto unknown distress level of Icelandic people with insulin requiring diabetes. DESIGN: Methodological research design. SETTING: Diabetes clinics. PARTICIPANTS: People with insulin-dependent diabetes, between 18 and 61 years. METHODS: All instruments were translated using a back-translation technique. Participants answered three consecutive questionnaires in succession, the PAID scale, the diabetes empowerment scale (DES) and the diabetes knowledge test (DKT). Principical component analysis with varimax rotation was conducted on the PAID scale to identify latent factors. RESULTS: Factor analysis revealed two factors: (a) distress in relation to life with diabetes, with Cronbach alpha coefficient of 0.93 and (b) distress in relation to management of diabetes, with Cronbach alpha coefficient of 0.88, for PAID overall Cronbach alpha coefficient was 0.94. PAID showed neither floor nor ceilings effects. Propositions set to indicate validity were generally met. However, PAID's factor structure and predictive validity needs to be tested further. CONCLUSIONS: The Icelandic version of PAID is sufficiently psychometrically robust. PAID is simple to administer and by using the scale clinicians can identify people at risk for developing diabetes-related distress. The results are comparable to results from studies in other countries using the PAID scale.     

Japanese Elderly Diabetes Intervention Trial (J-EDIT)

Treatment goals of medical care for the elderly patients with diabetes mellitus are maintaining high quality of life and elongating healthy longevity. In order to clarify how the elderly patients with diabetes mellitus should be treated for those purposes, a randomized controlled intervention study using 1,173 Japanese elderly patients with diabetes mellitus is now performing. All subjects have moderate or severe glucose intolerance. Subjects have been divided into two groups, ordinary treatment group and treatment group treated as same as adult patients with diabetes mellitus. The study has not been finished. Therefore, intermediate results were demonstrated and expectation for the study were discussed.     

The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1-PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1-PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.     

Diabetes reporting as a cause of death: results from the Translating Research Into Action for Diabetes (TRIAD) study

OBJECTIVE: To determine the frequency of reporting of diabetes on death certificates of decedents with known diabetes, define factors associated with reporting of diabetes, and describe trends in reporting over time. RESEARCH DESIGN AND METHODS: Data were obtained from 11,927 participants with diabetes who were enrolled in the Translating Research Into Action for Diabetes study, a multicenter prospective observational study of diabetes care in managed care. Data on decedents (n = 540) were obtained from the National Death Index. The primary dependent variable was the presence of ICD-10 codes for diabetes on the death certificate. Covariates included age at death, sex, race/ethnicity, education, income, duration of diabetes, type of diabetes, diabetes treatment, smoking status, and number of comorbidities. RESULTS: Diabetes was recorded on 39% of death certificates and as the underlying cause of death for 10% of decedents with diabetes. Diabetes was significantly less likely to be reported on the death certificates of decedents with diabetes dying of cancer. Predictors of recording diabetes anywhere on the death certificate included longer duration of diabetes and insulin treatment. Longer duration of diabetes, insulin treatment, and fewer comorbidities were associated with recording of diabetes as the underlying cause of death. CONCLUSIONS: Diabetes is much more likely to be reported on the death certificates of diabetic individuals who die of cardiovascular causes. Reporting of diabetes on death certificates has been stable over time. Death certificates underestimate the prevalence of diabetes among decedents and present a biased picture of the causes of death among people with diabetes.     

The diabetes health care of Aboriginal people in South Australia (Part 1)

Although type 2 diabetes is a recognised health priority in South Australia, Aboriginal people with diabetes do not utilise the mainstream diabetes health services on a regular basis for health care. This means that Aboriginal clients have the potential to develop diabetes-related problems and, furthermore, are not in a position to make informed decisions about health care issues. This lack of client empowerment is contrary to the goals of contemporary diabetes health care and, as a result, Aboriginal clients suffer the consequences of ineffective management with a compromised lifestyle. To identify how this situation might be improved, a qualitative study funded by Diabetes Australia was undertaken in South Australia. The overall goal was, firstly, to identify the reasons why Aboriginal people with diabetes do not attend mainstream health agencies on a regular basis and secondly, if possible, to improve attendance. Thus, Aboriginal health professionals (n = 43) were recruited from the 8 statistical divisions of South Australia and interviewed about Aboriginal diabetes health care issues. In Part 1 of this series, the research findings indicated the beliefs and attitudes held by clients about diabetes, their lack of knowledge about management issues, their responses to diabetes, the effects of diabetes on their lifestyle and the strategies that diabetes health professionals used to help their clients deal with diabetes health issues. In Part 2 the research findings indicated the importance of the Aboriginal health worker to the successful diabetes management of Aboriginal clients, the constraints that affect the delivery of diabetes health care and the recommendations made by health professionals to improve the standard of diabetes health services.     

The diabetes health care of Aboriginal people in South Australia (Part 2)

Although type 2 diabetes is a recognised health priority in South Australia, Aboriginal people with diabetes do not utilise the mainstream diabetes health services on a regular basis for health care. This means that Aboriginal clients have the potential to develop diabetes-related problems and, furthermore, are not in a position to make informed decisions about health care issues. This lack of client empowerment is contrary to the goals of contemporary diabetes health care and, as a result, Aboriginal clients suffer the consequences of ineffective management with a compromised lifestyle. To identify how this situation might be improved, a qualitative study funded by Diabetes Australia was undertaken in South Australia. The overall goal was, firstly, to identify the reasons why Aboriginal people with diabetes do not attend mainstream health agencies on a regular basis and secondly, if possible, to improve attendance. Thus, Aboriginal health professionals (n = 43) were recruited from the 8 statistical divisions of South Australia and interviewed about Aboriginal diabetes health care issues. In Part 1 of this series, the research findings indicated the beliefs and attitudes held by clients about diabetes, their lack of knowledge about management issues, their responses to diabetes, the effects of diabetes on their lifestyle and the strategies that diabetes health professionals used to help their clients deal with diabetes health issues. In Part 2 the research findings indicated the importance of the Aboriginal health worker to the successful diabetes management of Aboriginal clients, the constraints that affect the delivery of diabetes health care and the recommendations made by health professionals to improve the standard of diabetes health services.     

Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse

Genetic analysis of the development of diabetes and insulitis has been performed in the nonobese diabetic (NOD) mouse strain, a model of insulin-dependent (type I) diabetes mellitus. (NOD X C57BL/10)F1, F2, and (F1 X NOD) first-, second-, and third-backcross generations were studied. The data obtained were consistent with the hypothesis that diabetes is controlled by at least three functionally recessive diabetogenic genes, or gene complexes, one of which is linked to the MHC of the NOD. In contrast, pancreatic inflammation leading to insulitis was found to be controlled by a single incompletely dominant gene. One of the two diabetogenic loci that is not linked to the MHC appears to be essential for the development of severe insulitis. This diabetogenic gene may be identical to the gene that controls the initiation of the autoimmune response that progresses to insulitis. Although this gene appears to be functionally recessive in its control of diabetes, it is incompletely dominant in its control of insulitis. The MHC-linked diabetogenic gene, although not required for the development of insulitis, apparently influences the progression of the autoimmune response since NOD MHC homozygotes in the backcross generations displayed the highest incidence and most severe cases of insulitis. Interestingly, we have found two MHC heterozygous backcross females that have become diabetic, suggesting that either the MHC-linked diabetogenic gene is not strictly recessive or that a recombination event has occurred between the diabetogenic gene and the K or I-A regions of the MHC. The third diabetogenic locus appears to influence the progression of severe insulitis to overt diabetes. In animals homozygous at this locus, diabetes may result from a decreased ability to develop a protective suppressor response to the autoimmune process.     

Rosiglitazone (BRL-49653)

Rosiglitazone, a thiazolidinedion antidiabetic agent, improves insulin resistance in patients with type 2 diabetes mellitus. Rosiglitazone binds to PPAR-gamma with high affinity and the in vivo antidiabetic potency of rosiglitazone is correlated with its high biding affinity. In animal models of insulin resistence, rosiglitazone decreased plasma glucose, triglyceride and insulin levels and also prevented diabetic nephropathy and pancreatic islet cell degeneration. In clinical trials in patients with type 2 diabetes mellitus, rosiglitazone, 2 to 12 mg/day (as a single daily dose or 2 divided daily doses), improved glycemic control as demonstrated, by decreases in fasting plasma glucose and HbA1C levels. Rosiglitazone did not appear to increase the risk of hypoglycemia and there was no evidence of hepatotoxicity in pre-clinical trials.     

Glucagon-like peptide-1(GLP-1)

Glucagon-like peptide-1(GLP-1), an intestinal hormone secreted by L cells in response to luminal nutrients(carbohydrate and fat), enhances glucose-induced insulin secretion. Impairment of glucose-induced insulin secretion in patients with type 2 diabetes can be restored to near-normal by GLP-1 administration. In addition, GLP-1 possesses multiple biological effects which are favorable for the treatment of type 2 diabetes: inhibition of glucagon secretion, slowing of gastric emptying, reduction of appetite and food intake, upregulation of genes essential for insulin secretion(glucokinase, GLUT-2 etc), and beta cell proliferation and differentiation. Some long-acting GLP-1 derivatives which are resistant to the degradation by enzyme dipeptidyl peptidase-IV are currently under the clinical trial and are reportedly promising for the treatment of type 2 diabetes, because of impressive effects on glycemic control, availability by oral administration and very few adverse effects.     

Association of acculturation levels and prevalence of diabetes in the multi-ethnic study of atherosclerosis (MESA)

OBJECTIVE—The prevalence of type 2 diabetes among Hispanic and Asian Americans is increasing. These groups are largely comprised of immigrants who may be undergoing behavioral and lifestyle changes associated with development of diabetes. We studied the association between acculturation and diabetes in a population sample of 708 Mexican-origin Hispanics, 547 non–Mexican-origin Hispanics, and 737 Chinese participants in the Multi-Ethnic Study of Atherosclerosis (MESA).RESEARCH DESIGN AND METHODS—Diabetes was defined as fasting glucose ≥126 mg/dl and/or use of antidiabetic medications. An acculturation score was calculated for all participants using nativity, years living in the U.S., and language spoken at home. The score ranged from 0 to 5 (0 = least acculturated and 5 = most acculturated). Relative risk regression was used to estimate the association between acculturation and diabetes.RESULTS—For non–Mexican-origin Hispanics, the prevalence of diabetes was positively associated with acculturation score, after adjustment for sociodemographics. The prevalence of diabetes was significantly higher among the most acculturated versus the least acculturated non–Mexican-origin Hispanics (prevalence ratio 2.49 [95% CI 1.14−5.44]); the higher the acculturation score is, the higher the prevalence of diabetes (P for trend 0.059). This relationship between acculturation and diabetes was partly attenuated after adjustment for BMI or diet. Diabetes prevalence was not related to acculturation among Chinese or Mexican-origin Hispanics.CONCLUSIONS—Among non–Mexican-origin Hispanics in MESA, greater acculturation is associated with higher diabetes prevalence. The relation is at least partly mediated by BMI and diet. Acculturation is a factor that should be considered when predictors of diabetes in racial/ethnic groups are examined.The prevalence of diabetes is increasing in Hispanic and Chinese Americans (1,2), groups comprised largely of immigrants. Immigration and subsequent behavior changes may contribute to the development of diabetes. Acculturation has been broadly defined as “the process by which individuals adopt the attitudes, values, customs, beliefs, and behaviors of another culture” (3). More recently, there has been recognition of the multidimensional aspects of acculturation (4) and the fact that the health effects of acculturation vary by country of origin and the health behavior or outcome being studied (5). Prior studies have suggested a relationship between acculturation, lifestyle behaviors, and other risk factors that may result in higher cardiovascular risk for immigrants in the U.S. (6,7). However, the associations between immigration, acculturation, and diabetes among U.S. immigrants have not been as well studied.Studies that have looked at the association between acculturation and diabetes have found differing results, depending on the immigrants’ country of origin. Among Japanese Americans, studies suggest that increasing acculturation is associated with higher diabetes risk (8,9). One study of Arab Americans found that a lack of acculturation is a risk factor for diabetes (10). Data on the association between acculturation and diabetes in Hispanics have not been consistent, and few studies have examined differences by country of origin (11). Understanding the consequences of acculturation for diabetes and its risks factors would have important implications for preventing diabetes in a large and growing portion of the U.S. population.The main objective of this study was to examine the hypothesis that diabetes prevalence among Hispanic and Chinese participants in the Multi-Ethnic Study of Atherosclerosis (MESA) differs by acculturation status. Based on prior studies showing that acculturation is associated with greater BMI among Asians and Hispanics (12,13), we hypothesized that greater acculturation would be associated with a higher diabetes prevalence among Hispanics and Chinese in MESA and that BMI would be part of the mechanism. We also explored the roles of physical activity and diet in mediating this association and examined whether associations between acculturation and diabetes differed by race/ethnicity and country of origin among Hispanics.     

Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging.

N(epsilon)-(Carboxymethyl)lysine (CML), a major product of oxidative modification of glycated proteins, has been suggested to represent a general marker of oxidative stress and long-term damage to proteins in aging, atherosclerosis, and diabetes. To investigate the occurrence and distribution of CML in humans an antiserum specifically recognizing protein-bound CML was generated. The oxidative formation of CML from glycated proteins was reduced by lipoic acid, aminoguanidine, superoxide dismutase, catalase, and particularly vitamin E and desferrioxamine. Immunolocalization of CML in skin, lung, heart, kidney, intestine, intervertebral discs, and particularly in arteries provided evidence for an age-dependent increase in CML accumulation in distinct locations, and acceleration of this process in diabetes. Intense staining of the arterial wall and particularly the elastic membrane was found. High levels of CML modification were observed within atherosclerotic plaques and in foam cells. The preferential location of CML immunoreactivity in lesions may indicate the contribution of glycoxidation to the processes occurring in diabetes and aging. Additionally, we found increased CML content in serum proteins in diabetic patients. The strong dependence of CML formation on oxidative conditions together with the increased occurrence of CML in diabetic serum and tissue proteins suggest a role for CML as endogenous biomarker for oxidative damage.     

Platelet associated IgG (PA IgG) in patients with insulin dependent (type 1) diabetes mellitus

Increased levels of Platelet Associated IgG have been found in 30% of patients with insulin dependent (type 1) diabetes mellitus, closely associated with the simultaneous presence in the serum of insulin antibodies and immune complexes. It is suggested that the increase in PA IgG levels may be of importance in the occurrence of the platelet abnormalities observed in diabetes mellitus.     

Inflammation and the Incidence of Type 2 Diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

Many studies have documented associations between inflammation and type 2 diabetes incidence. We assessed potential variability in this association in the major U.S. racial/ethnic groups.

RESEARCH DESIGN AND METHODS

Incident type 2 diabetes was assessed among men and women aged 45–84 years without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin (IL)-6, fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000–2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose ≥126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HRs) by quartiles of CRP, IL-6, and fibrinogen.

RESULTS

Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, and 20.7% Hispanic), 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1,000 person-years). CRP, IL-6, and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however, quartile 4 (versus quartile 1) of IL-6 (HR 1.5 [95% CI 1.1–2.2]) and CRP (1.7 [1.3–2.4]) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants.

CONCLUSIONS

Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multiethnic American sample.A number of prospective studies (1–8) have demonstrated an association between high levels of inflammation and the development of type 2 diabetes. In this report, we assess three inflammatory markers: C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen. CRP is an acute-phase reactant mainly produced in the liver. Recent studies have shown that CRP can also be produced by fat cells (9), which raises the possibility that CRP may simply be a marker of obesity in people who go on to develop diabetes. Fibrinogen is involved in clotting but is also an acute-phase reactant and has been previously linked to incident diabetes (8). IL-6 is made by leukocytes and other tissues that play a role in glucose homeostasis, including pancreatic islet cells, hepatocytes, adipocytes, and skeletal muscle cells, and is associated with incident diabetes (10). The graded positive association between most inflammatory markers and diabetes incidence remains significant following adjustment for established diabetes risk factors. However, a study (11) in the Pima population showed no association between inflammatory markers and the risk of diabetes after adjusting for established risk factors for diabetes. Although a sizable number of studies have documented the inflammatory marker–diabetes association, studies on ethnic/racial variations in this association are limited, despite the well-documented increased prevalence of diabetes in nonwhite populations in the U.S. (12). The aims of this analysis are 1) to explore the ability of CRP, IL-6, and fibrinogen to predict the incidence of diabetes in a prospective, multiethnic cohort and 2) to determine the extent to which observed associations are similar across racial/ethnic groups. We also consider whether observed associations are independent of the major known risk factors for diabetes (obesity, family history, insulin resistance, hypertension, age, and physical inactivity) (13).