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Objective: The role of adiponectin in the natural history of diabetes is not well characterized. We set out to characterize prediagnosis trajectories of adiponectin in individuals who develop type 2 diabetes.Research Design and Methods: In a case-cohort study (335 incident diabetes case and 2,474 noncase subjects) nested in the Whitehall II study, serum adiponectin was measured up to three times per participant (1991-1993, 1997-1999, and 2003-2004). Multilevel models adjusted for age and ethnicity were fitted to assess 13-year trajectories of log-transformed adiponectin preceding diabetes diagnosis or a randomly selected time point during follow-up (year(0)) based on 755/5,095 (case/noncase) person-examinations.Results: Adiponectin levels were lower in diabetes case than in noncase subjects (median 7,141 [interquartile range 5,187-10,304] vs. 8,818 [6,535-12,369] ng/mL at baseline, P < 0.0001). Control subjects showed a modest decline in adiponectin throughout follow-up (0.3% per year, P < 0.0001) at higher levels in women than in men (difference at year(0): 5,358 ng/mL, P < 0.0001). Female case and early-onset case (age at diagnosis <52 years) subjects had a steeper decline than control subjects (slope difference -1.1% per year, P = 0.001 in females, -1.6% per year in early-onset case subjects, P = 0.034). In men, adiponectin slopes for case and noncase subjects were parallel. The slope differences by diabetes onset were largely attenuated after adjustment for changes in obesity, whereas the sex-specific slope differences were independent of obesity.Conclusions: Lower adiponectin levels were observed already a decade before the diagnosis of diabetes. The marked sex difference in trajectories suggests that sex-specific mechanisms affect the association between adiponectin levels and diabetes development. [ABSTRACT FROM AUTHOR]

Objective: To examine antidepressant use before and after the diagnosis of diabetes.Research Design and Methods: This study was a longitudinal analysis of diabetic and nondiabetic groups selected from a prospective cohort study of 151,618 men and women in Finland (the Finnish Public Sector Study, 1995-2005). We analyzed the use of antidepressants in those 493 individuals who developed type 2 diabetes and their 2,450 matched nondiabetic control subjects for each year during a period covering 4 years before and 4 years after the diagnosis. For comparison, we undertook a corresponding analysis on 748 individuals who developed cancer and their 3,730 matched control subjects.Results: In multilevel longitudinal models, the odds ratio for antidepressant use in those who developed diabetes was 2.00 (95% CI 1.57-2.55) times greater than that in nondiabetic subjects. The relative difference in antidepressant use between these groups was similar before and after the diabetes diagnosis except for a temporary peak in antidepressant use at the year of the diagnosis (OR 2.66 [95% CI 1.94-3.65]). In incident cancer case subjects, antidepressant use substantially increased after the cancer diagnosis, demonstrating that our analysis was sensitive for detecting long-term changes in antidepressant trajectories when they existed.Conclusions: Awareness of the diagnosis of type 2 diabetes may temporarily increase the risk of depressive symptoms. Further research is needed to determine whether more prevalent use of antidepressants noted before the diagnosis of diabetes relates to effects of depression, side effects of antidepressant use, or a common causal pathway for depression and diabetes. [ABSTRACT FROM AUTHOR]

Objective: Interleukin-1 receptor antagonist (IL-1Ra), a natural inhibitor of interleukin-1 beta, has been shown to improve beta-cell function and glycemic control in patients with type 2 diabetes. The aim of this study was to investigate whether baseline systemic levels of IL-1Ra are associated with incident type 2 diabetes during more than 10 years of follow-up.Research Design and Methods: We measured serum IL-1Ra concentrations in a nested case-control study (181 case and 376 age-, sex-, and BMI-matched normoglycemic control subjects) within the Whitehall II cohort (U.K.).Results: IL-1Ra concentrations were higher in case subjects (P = 0.0006) and associated with incident type 2 diabetes (odds ratio for a 1-SD increase of IL-1Ra 1.48 [95% CI 1.21-1.80]). This association remained significant after adjustment for multiple potential confounders but was attenuated by adjusting for 2-h glucose.Conclusions: Our findings indicate that individuals who will develop type 2 diabetes are characterized by a complex immune activation that also includes upregulation of the anti-inflammatory cytokine IL-1Ra. [ABSTRACT FROM AUTHOR]

Objective: Higher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants' baseline glycemic state., Research Design and Methods: In this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested., Results: At baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non-CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm-higher baseline HR level was associated with an 11.4% higher rate of all-cause mortality (95% CI 1.0-22.9%; P = 0.032). Glycemic state did not modify associations., Conclusions: Changes in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia., (© 2021 by the American Diabetes Association.)

Objective: Autonomic nervous system dysfunction is associated with impaired glucose metabolism, but the temporality of this association remains unclear in individuals without diabetes. We investigated the association of autonomic function with 5-year changes in glucose metabolism in individuals without diabetes., Research Design and Methods: Analyses were based on 9,000 person-examinations for 3,631 participants without diabetes in the Whitehall II cohort. Measures of autonomic function included 5-min resting heart rate and six heart rate variability (HRV) indices. Associations between baseline autonomic function measures and 5-year changes in fasting and 2-h plasma glucose, serum insulin concentrations, insulin sensitivity (insulin sensitivity index [ISI 0-120 ] and HOMA of insulin sensitivity), and β-cell function (HOMA of β-cell function) were estimated in models adjusting for age, sex, ethnicity, metabolic factors, and medication., Results: A 10-bpm higher resting heart rate was associated with 5-year changes in fasting and 2-h insulin and ISI 0-120 of 3.3% change (95% CI 1.8; 4.8), P < 0.001; 3.3% change (1.3; 5.3), P = 0.001; and -1.4% change (-2.4; -0.3), P = 0.009, respectively. In models adjusted for age, sex, and ethnicity, higher baseline values of several HRV indices were associated with a 5-year decrease in fasting and 2-h insulin and ISI 0-120 . However, significance was lost by full adjustment. A majority of HRV indices exhibited a trend toward higher values being associated with lower insulin levels and higher insulin sensitivity., Conclusions: Higher resting heart rate in individuals without diabetes is associated with future unfavorable changes in insulin levels and insulin sensitivity. Associations may be mediated via autonomic function; however, results are inconclusive. Resting heart rate may be a risk marker for future pathophysiological changes in glucose metabolism., (© 2019 by the American Diabetes Association.)

Objective: The extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS)., Research Design and Methods: In this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up., Results: Over the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25-3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex., Conclusions: Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.

OBJECTIVE To compare screen-detected diabetes prevalence and the degree of diagnostic agreement by ethnicity with the current oral glucose tolerance test (OGTT)-based and newly proposed A1C-based diagnostic criteria. RESEARCH DESIGN AND METHODS Six studies (1999-2009) from Denmark, the U.K., Australia, Greenland, Kenya, and India were tested for the probability of an A1C > or =6.5% among diabetic case subjects based on an OGTT. The difference in probability between centers was analyzed by logistic regression adjusting for relevant confounders. RESULTS Diabetes prevalence was lower with the A1C-based diagnostic criteria in four of six studies. The probability of an A1C > or =6.5% among OGTT-diagnosed case subjects ranged widely (17.0-78.0%) by study center. Differences in diagnostic agreement between ethnic subgroups in the U.K. study were of the same magnitude as between-country comparisons. CONCLUSIONS A shift to an A1C-based diagnosis for diabetes will have substantially different consequences for diabetes prevalence across ethnic groups and populations.

Objective: Gestational diabetes is a risk factor for large-for-gestational-age (LGA) newborns, but many LGA babies are born to mothers with normal glucose tolerance. We aimed to clarify the association of maternal glycemia across the whole distribution with birth weight and risk of LGA births in mothers with normal glucose tolerance., Research Design and Methods: We undertook a population-based gestational diabetes screening in an urban area of Hungary in 2002-2005. All singleton pregnancies of mothers >or=18 years of age, without known diabetes or gestational diabetes (World Health Organization criteria) and data on a 75-g oral glucose tolerance test at 22-30 weeks of gestation, were included (n = 3,787, 78.9% of the target population). LGA was determined as birth weight greater than the 90th percentile using national sex- and gestational age-specific charts., Results: Mean +/- SD maternal age was 30 +/- 4 years, BMI was 22.6 +/- 4.0 kg/m(2), fasting blood glucose was 4.5 +/- 0.5 mmol/l, and postload glucose was 5.5 +/- 1.0 mmol/l. The mean birth weight was 3,450 +/- 476 g at 39.2 +/- 1.2 weeks of gestation. There was a U-shaped association of maternal fasting glucose with birth weight (P(curve) = 0.004) and risk of having an LGA baby (lowest values between 4 and 4.5 mmol/l, P(curve) = 0.0004) with little change after adjustments for clinical characteristics. The association of postload glucose with birth weight (P = 0.03) and the risk of an LGA baby (P = 0.09) was weaker and linear., Conclusions: Both low and high fasting glucose values at 22-30 weeks of gestation are associated with increased risk of an LGA newborn. We suggest that the excess risk related to low glucose reflects the increased use of nutrients by LGA fetuses that also affects the mothers' fasting glucose.

Objective: To evaluate neural dysfunction in subjects with impaired glucose tolerance (IGT)., Research Design and Methods: For this study, 46 subjects with IGT and 45 healthy volunteers underwent detailed neurological assessment. Cardiovascular autonomic function was assessed by standard cardiovascular reflex tests, and heart rate variability was characterized by the triangle index. Sensory nerve function was assessed using Neurometer (for current perception threshold) and Medoc devices. Peak plantar pressure was measured by dynamic pedobarography, and symptoms were graded using the neuropathy total symptom score., Results: Subjects with IGT had significantly greater abnormalities detected by four of five cardiovascular reflex tests and greater heart rate variability characterized by the triangle index. They had a higher frequency of both hyperesthesia and hypoesthesia as detected by current perception threshold testing at 5 Hz, as well as increased heat detection thresholds., Conclusions: This study provides evidence that subclinical neural dysfunction is present in subjects with IGT and can be detected noninvasively. Cardiovascular autonomic neuropathy may contribute to increased cardiovascular risk in IGT subjects.

Objective: In the U.S., both primary care and specialist physicians share in the care of type 1 diabetic patients, often in an informal collaboration. In Hungary, however, type 1 diabetic patients are generally managed in special centralized diabetes units. These different treatment settings may lead to different health care practices and outcomes. To determine if this is true, diabetes care indicators and complications were compared across representative study populations from the 2 countries., Research Design and Methods: The Pittsburgh Epidemiology of Diabetes Complications Study (EDC) is a prospective cohort of childhood-onset type 1 diabetic patients. DiabCare Hungary, a multicenter cross-sectional study, was developed for quality control purposes and provides a nationwide data set of diabetic patients. We identified 2 comparable populations (EDC, n = 416; DiabCare, n = 405) in terms of age (> or =14 years) and age at onset (<17 years)., Results: EDC patients were less likely to receive diabetes education (P<0.0001), see an ophthalmologist (P<0.0001), be treated by diabetologists (P<0.0001), or perform self-monitoring of blood glucose (P<0.0001). They were more likely to use conservative insulin regimens (i.e., 1-2 injections/day, P<0.0001) and have a higher glycated hemoglobin (P< 0.0001). DiabCare patients more often experienced severe hypoglycemia (P<0.01) and had a lower prevalence of proliferative retinopathy (P<0.0001), legal blindness (P<0.05), and albuminuria (> or =30 mg/day P<0.01). No significant differences in macrovascular complications were seen, although rates were generally low, Conclusions: These data suggest that the 2 populations differ by their diabetes care practices, degree of glycemic control, and microvascular complication status.