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Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from three individuals with ICI-related T1D, and their histopathological data were compared those from three patients who had received ICI therapy but did not develop T1D (non-T1D) and seven normal glucose-tolerant subjects as control subjects. All ICI-related T1D patients had susceptible HLA haplotypes. In ICI-related T1D, the β-cell area decreased and the α-cell area increased compared with non-T1D and control subjects. The number of CD3-positive cells around islets increased in ICI-related T1D and non-T1D compared with control subjects, while the number of CD68-positive cells around islets increased in ICI-related T1D compared with non-T1D and control subjects. The expression ratios of programmed death-ligand 1 (PD-L1) on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while PD-L1 expression was observed in most cells of pancreatic islets in control subjects. This study, therefore, indicates that ICI therapy itself could reduce PD-L1 expression on islets in all subjects, which may be related to β-cell vulnerability. In addition, we showed that absence of PD-L1 expression on β-cells, genetic susceptibility, and infiltration of macrophages as well as T lymphocytes around islets might be responsible for T1D onset.ARTICLE HIGHLIGHTS

BACKGROUND: Healthy plant-based diet index (hPDI) is associated with a lower risk of cardiometabolic conditions, but its association as well as interactions with microbiome have not been elucidated. OBJECTIVES: We aimed to investigate the interrelations between hPDI, gut microbiome, and cardiometabolic risk markers. METHODS: hPDI was derived from dietary assessments by a validated FFQ and was examined in relation to metagenomic profiles of 911 fecal samples collected from 303 men aged 71 ± 4 y with an average BMI (in kg/m(2)) of 25.2 ± 3.6 in the Men's Lifestyle Validation Study. Principal coordinate (PCo) analysis based on Bray–Curtis dissimilarity was conducted, and interactions between hPDI and PCo were examined by using a metabolic risk score composed of blood lipids, BMI, and glycated hemoglobin. RESULTS: After multivariable adjustment, hPDI was significantly associated with the relative abundance of 7 species and 9 pathways. In particular, higher hPDI was significantly associated with a higher relative abundance of Bacteroides cellulosilyticus and Eubacterium eligens, amino acid biosynthesis pathways (l-isoleucine biosynthesis I and III and l-valine biosynthesis), and the pathway of pyruvate fermentation to isobutanol. A favorable association between hPDI and the metabolic risk score was more pronounced among men with a higher PCo characterized by higher abundance of Bacteroides uniformis and lower abundance of Prevotella copri. At the individual species level, a similar interaction was also observed between hPDI and P. copri, as well as with Clostridium clostridioforme or Blautia hydrogenotrophica (all P-interaction

To evaluate the association of plant-based diet index (PDI) with early onset of natural menopause in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).We conducted a prospective study with a mean follow-up time of 20 years among premenopausal women living across the US. Participants of the NHS (n = 121,701) and NHSII (n = 116,429) were included from 1984 (age mean [standard deviation]; 44.9 [4.3]) and 1991 (age mean [standard deviation]; 36.4 [4.6]), respectively. Early menopause was self-reported and defined as natural menopause before age 45 years. PDI was derived from semiquantitative food frequency questionnaires administered every 4 years. Cox proportional hazards models were used to assess the association between PDI in quintiles and early menopause in NHS and NHSII separately, and fixed-effect models to pool the results from both cohorts.During follow-up, 715 and 2,185 women experienced early natural menopause in NHS and NHSII, respectively. After adjustment for potential confounders, no association was observed between PDI and incidence of early natural menopause in either cohort, or when pooling the results from both cohorts, with an exception for unhealthy plant-based diet index which was associated with higher risk of early menopause with increasing levels of consumption (P trend = 0.04).Adherence to PDI was not associated with timing of menopause while unhealthy plant-based diet might be associated with higher risk of experiencing early menopause.

OBJECTIVE To evaluate the association of plant-based diet index (PDI) with early onset of natural menopause in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). METHODS We conducted a prospective study with a mean follow-up time of 20 years among premenopausal women living across the US. Participants of the NHS (n = 121,701) and NHSII (n = 116,429) were included from 1984 (age mean [standard deviation]; 44.9 [4.3]) and 1991 (age mean [standard deviation]; 36.4 [4.6]), respectively. Early menopause was self-reported and defined as natural menopause before age 45 years. PDI was derived from semiquantitative food frequency questionnaires administered every 4 years. Cox proportional hazards models were used to assess the association between PDI in quintiles and early menopause in NHS and NHSII separately, and fixed-effect models to pool the results from both cohorts. RESULTS During follow-up, 715 and 2,185 women experienced early natural menopause in NHS and NHSII, respectively. After adjustment for potential confounders, no association was observed between PDI and incidence of early natural menopause in either cohort, or when pooling the results from both cohorts, with an exception for unhealthy plant-based diet index which was associated with higher risk of early menopause with increasing levels of consumption (P trend = 0.04). CONCLUSION Adherence to PDI was not associated with timing of menopause while unhealthy plant-based diet might be associated with higher risk of experiencing early menopause.

IntroductionThis study aimed to identify the associations between lifestyle factors and intrapancreatic fat deposition in patients with type 2 diabetes.Research design and methodsThe participants were 185 patients with type 2 diabetes who were hospitalized at Osaka University Hospital between 2008 and 2020 and underwent abdominal CT during hospitalization. Information regarding lifestyle factors, including the number of meals consumed per day, snacking habits, exercise habits, exercise at work, smoking habits, alcohol intake, insomnia, sleep apnea syndrome, and night-shift working, was acquired from self-administered questionnaires or medical records. We measured the mean CT values for the pancreas (P), liver (L), and spleen (S), and the visceral fat area (VFA), and quantified intrapancreatic and liver ectopic fat accumulation as P−S and L−S, respectively.ResultsAfter adjustment for age, sex, hemoglobin A1c, and body mass index (BMI), participants who consumed two meals per day had significantly lower P−S (higher intrapancreatic fat deposition, p=0.02) than those who consumed three meals per day. There were no significant associations between the number of meals consumed and liver ectopic fat accumulation and VFA (p=0.73 and p=0.67, respectively).ConclusionsPatients with diabetes who consumed two meals per day showed greater intrapancreatic fat deposition than those who consumed three meals per day, even after adjustment for BMI. These findings support the current guideline for diabetes treatment that skipping meals should be avoided.

AIMS/HYPOTHESIS: Plant-based diets, especially when rich in healthy plant foods, have been associated with a lower risk of type 2 diabetes. However, whether plasma metabolite profiles related to plant-based diets reflect this association was unknown. The aim of this study was to identify the plasma metabolite profiles related to plant-based diets, and to evaluate the associations between the identified metabolite profiles and the risk of type 2 diabetes. METHODS: Within three prospective cohorts (Nurses’ Health Study, Nurses’ Health Study II and Health Professionals Follow-up Study), we measured plasma metabolites from 10,684 participants using high-throughput LC MS. Adherence to plant-based diets was assessed by three indices derived from the food frequency questionnaire: an overall Plant-based Diet Index (PDI), a Healthful Plant-based Diet Index (hPDI), and an Unhealthy Plant-based Diet Index (uPDI). Multi-metabolite profiles related to plant-based diet were identified using elastic net regression with a training/testing approach. The prospective associations between metabolite profiles and incident type 2 diabetes were evaluated using multivariable Cox proportional hazards regression. Metabolites potentially mediating the association between plant-based diets and type 2 diabetes risk were further identified. RESULTS: We identified multi-metabolite profiles comprising 55 metabolites for PDI, 93 metabolites for hPDI and 75 metabolites for uPDI. Metabolite profile scores based on the identified metabolite profiles were correlated with the corresponding diet index (Pearson r = 0.33–0.35 for PDI, 0.41–0.45 for hPDI, and 0.37–0.38 for uPDI, all p < 0.001). Metabolite profile scores of PDI (HR per 1 SD higher = 0.81 [95% CI 0.75, 0.88]) and hPDI (HR per 1 SD higher = 0.77 [95% CI 0.71, 0.84]) showed an inverse association with incident type 2 diabetes, whereas the metabolite profile score for uPDI was not associated with the risk. Mutual adjustment for metabolites selected in the metabolite profiles, including trigonelline, hippurate, isoleucine and a subset of triacylglycerols, attenuated the associations of diet indices PDI and hPDI with lower type 2 diabetes risk. The explainable proportion of PDI/hPDI-related diabetes risk by these metabolites ranged between 8.5% and 37.2% (all p < 0.05). CONCLUSIONS/INTERPRETATION: Plasma metabolite profiles related to plant-based diets, especially a healthy plant-based diet, were associated with a lower risk of type 2 diabetes among a generally healthy population. Our findings support the beneficial role of healthy plant-based diets in diabetes prevention and provide new insights for future investigation.

OBJECTIVE To identify sleep duration trajectories from early to middle adulthood and their associations with incident type 2 diabetes. RESEARCH DESIGN AND METHODS Using a group-based modeling approach, we identified sleep duration trajectories based on sleep duration in ages 20–25, 26–35, 36–45, and 46+ years, which were retrospectively assessed in 2009 among 60,068 women from the Nurses’ Health Study II (median age 54.9 years) who were free of diabetes, cardiovascular disease, and cancer. We investigated the prospective associations between sleep duration trajectories and diabetes risk (2009–2017) using multivariable Cox proportional hazards models. RESULTS We documented 1,797 incident diabetes cases over a median follow-up of 7.8 years (442,437 person-years). Six sleep duration trajectories were identified: persistent 5-, 6-, 7-, or 8-h sleep duration and increased or decreased sleep duration. After multivariable adjustment for diabetes risk factors, compared with the persistent 7-h sleep duration group, the hazard ratio was 1.43 (95% CI 1.10, 1.84) for the 5-h group, 1.17 (1.04, 1.33) for the 6-h group, 0.96 (0.84, 1.10) for the 8-h group, 1.33 (1.09, 1.61) for the increased sleep duration group, and 1.32 (1.10, 1.59) for the decreased sleep duration group. Additional adjustment for time-updated comorbidities and BMI attenuated these associations, although a significantly higher risk remained in the decreased sleep duration group (1.24 [1.03, 1.50]). CONCLUSIONS Persistent short sleep duration or changes in sleep duration from early to middle adulthood were associated with higher risk of type 2 diabetes in later life. These associations were weaker after obesity and metabolic comorbidities were accounted for.

We previously reported several factors that cross-sectionally correlate with treatment satisfaction in Japanese patients with type 2 diabetes visiting diabetes clinics. The aim of this study is to identify factors associated with longitudinal changes in treatment satisfaction in patients with type 2 diabetes.The study included 649 patients with type 2 diabetes treated with oral glucose-lowering agents who completed the first questionnaire in 2016. The collected data included scores from the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and other parameters regarding diabetes treatment. We analyzed 1-year longitudinal changes in DTSQ scores and investigated factors associated with these changes.Univariate linear regression analyses showed that changes in body weight, adherence to diet therapy, adherence to exercise therapy, cost burden, motivation for treatment, regularity of mealtimes, and perceived hypoglycemia correlated with changes in DTSQ scores. On the basis of multiple linear regression analyses, a decrease in hypoglycemia (β ± SE = - 0.394 ± 0.134, p = 0.0034), cost burden (β ± SE = - 0.934 ± 0.389, p = 0.017), and an increase in treatment motivation (β ± SE = 1.621 ± 0.606, p = 0.0077) correlated with DTSQ score increases, suggesting that motivation for treatment had the strongest impact on score increases. Subgroup analyses revealed that an increase in motivation for treatment most significantly correlated with a DTSQ score increase in obese and poor glycemic control groups, regardless of age.This is the first longitudinal study clarifying that an increase in motivation for treatment most strongly correlates with an increase in DTSQ score in patients with type 2 diabetes.

ImportanceThe current Dietary Guidelines for Americans recommend multiple healthy eating patterns. However, few studies have examined the associations of adherence to different dietary patterns with long-term risk of total and cause-specific mortality.ObjectiveTo examine the associations of dietary scores for 4 healthy eating patterns with risk of total and cause-specific mortality.Design, Setting, and ParticipantsThis prospective cohort study included initially healthy women from the Nurses’ Health Study (NHS; 1984-2020) and men from the Health Professionals Follow-up Study (HPFS; 1986-2020).ExposuresHealthy Eating Index 2015 (HEI-2015), Alternate Mediterranean Diet (AMED) score, Healthful Plant-based Diet Index (HPDI), and Alternate Healthy Eating Index (AHEI).Main Outcomes and MeasuresThe main outcomes were total and cause-specific mortality overall and stratified by race and ethnicity and other potential risk factors.ResultsThe final study sample included 75 230 women from the NHS (mean [SD] baseline age, 50.2 [7.2] years) and 44 085 men from the HPFS (mean [SD] baseline age, 53.3 [9.6] years). During a total of 3 559 056 person-years of follow-up, 31 263 women and 22 900 men died. When comparing the highest with the lowest quintiles, the pooled multivariable-adjusted HRs of total mortality were 0.81 (95% CI, 0.79-0.84) for HEI-2015, 0.82 (95% CI, 0.79-0.84) for AMED score, 0.86 (95% CI, 0.83-0.89) for HPDI, and 0.80 (95% CI, 0.77-0.82) for AHEI (P Conclusions and RelevanceIn this cohort study of 2 large prospective cohorts with up to 36 years of follow-up, greater adherence to various healthy eating patterns was consistently associated with lower risk of total and cause-specific mortality. These findings support the recommendations of Dietary Guidelines for Americans that multiple healthy eating patterns can be adapted to individual food traditions and preferences.

OBJECTIVES: Several plant-based foods have been associated with a lower risk of Crohn's disease (CD) and ulcerative colitis (UC), but not all plant-based foods are healthy. We aimed to examine the association of various plant-based diets with the risk of CD and UC. METHODS: We followed 169 945 women in the Nurses’ Health Study and Nurses’ Health Study II for up to 32 years. Plant-based diets were assessed by three indices derived from the food frequency questionnaires: an overall plant-based diet index (PDI), a healthful plant-based diet index (hPDI), and an unhealthful plant-based diet index (uPDI). Self-reported CD and UC were confirmed through medical record review. RESULTS: We documented 320 incident CD cases and 404 incident UC cases during 4 317 561 person-years. A higher hPDI was associated with a lower risk of UC (hazard ratio [HR] comparing extreme quintiles: 0.67; 95% confidence interval [CI]: 0.47–0.94; P-trend = 0.02). In contrast, the uPDI was associated with an increased risk of CD (HR: 1.67; 95% CI: 1.11–2.51; P-trend = 0.002) and UC (HR: 1.65; 95% CI: 1.15–2.35; P-trend = 0.03). Replacing refined grains, sugar-sweetened beverages, and sweets/desserts with an equal serving of fruits or vegetables was associated with lower risk of CD and UC. CONCLUSIONS: A healthful plant-based diet rich in fruits and vegetables was associated with a lower UC risk, whereas a plant-based diet emphasizing less healthy plant foods such as refined grains, sugar-sweetened beverages, and sweets/desserts was associated with a higher CD and UC risk. FUNDING SOURCES: National Institutes of Health.

Background: Plant-based diets have been associated with lower risk of type 2 diabetes mellitus and cardiovascular disease (CVD) and are recommended for both health and environmental benefits. However, the association between changes in plant-based diet quality and mortality remains unclear. Methods: We investigated the associations between 12-year changes (from 1986 to 1998) in plant-based diet quality assessed by 3 plant-based diet indices (score range, 18–90)—an overall plant-based diet index (PDI), a healthful PDI, and an unhealthful PDI—and subsequent total and cause-specific mortality (1998–2014). Participants were 49 407 women in the Nurses’ Health Study (NHS) and 25 907 men in the Health Professionals Follow-Up Study (HPFS) who were free from CVD and cancer in 1998. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Results: We documented 10 686 deaths including 2046 CVD deaths and 3091 cancer deaths in the NHS over 725 316 person-years of follow-up and 6490 deaths including 1872 CVD deaths and 1772 cancer deaths in the HPFS over 371 322 person-years of follow-up. Compared with participants whose indices remained stable, among those with the greatest increases in diet scores (highest quintile), the pooled multivariable-adjusted HRs for total mortality were 0.95 (95% CI, 0.90–1.00) for PDI, 0.90 (95% CI, 0.85–0.95) for healthful PDI, and 1.12 (95% CI, 1.07–1.18) for unhealthful PDI. Among participants with the greatest decrease (lowest quintile), the multivariable-adjusted HRs were 1.09 (95% CI, 1.04–1.15) for PDI, 1.10 (95% CI, 1.05–1.15) for healthful PDI, and 0.93 (95% CI, 0.88–0.98) for unhealthful PDI. For CVD mortality, the risk associated with a 10-point increase in each PDI was 7% lower (95% CI, 1–12%) for PDI, 9% lower (95% CI, 4–14%) for healthful PDI, and 8% higher (95% CI, 2–14%) for unhealthful PDI. There were no consistent associations between changes in plant-based diet indices and cancer mortality. Conclusions: Improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of an unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

Background: Plant-based diets have been associated with a lower risk of type 2 diabetes. However, the underlying mechanisms are not completely understood, and the evidence using objective approaches to assess the adherence of plant-based diets is limited. Methods: In the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study, we characterized the plasma metabolome related to plant-based diets and examined its association with the incidence of type 2 diabetes among 10 699 participants. Plasma metabolomic profiling was conducted by liquid chromatography-tandem mass spectrometry. Adherence to plant-based diets was assessed by three plant-based diet indices derived from the food frequency questionnaire: an overall plant-based diet index (PDI), a healthful PDI (hPDI), and an unhealthful PDI (uPDI). Metabolomic signatures reflecting the adherence to plant-based diets were created using elastic net regression, and their associations with risk of type 2 diabetes were subsequently evaluated using multivariable Cox proportional hazards regression. Results: Among 263 metabolites measured, nearly half were significantly associated with PDI (41.4%, 109 of 263), hPDI (51.7%, 136 of 263), and uPDI (40.3%, 106 of 263) after Bonferroni correction. We developed a metabolomic signature comprising 53 metabolites for PDI, 76 metabolites for hPDI, and 88 metabolites for uPDI, each robustly correlated with the corresponding diet index (r=0.34-0.36 for PDI, 0.43-0.44 for hPDI, and 0.36-0.37 for uPDI). We observed an inverse association of PDI metabolomic signature (HR 0.86, 95% CI 0.79-0.93 per one standard deviation) and hPDI metabolomic signature (0.79, 0.72-0.86) with type 2 diabetes risk after adjustment for body mass index and other potential confounders. These two inverse associations remained significant even further adjusting for the corresponding diet index PDI and hPDI. The metabolomic signature for uPDI was not associated with type 2 diabetes risk (1.00, 0.93-1.09). Conclusion: Plasma metabolome can robustly reflect adherence and metabolic response to plant-based diets. Metabolomic signatures reflecting greater adherence to an overall plant-based diet, especially a healthful plant-based diet, were associated with a lower risk of type 2 diabetes. These findings support and provide mechanistic insights on the important role of healthful plant-based diets in diabetes prevention.

ObjectiveTo determine whether a healthful plant-based diet is related to lower stroke risk, we examined the associations of plant-based diet quality with risk of total, ischemic, and hemorrhagic stroke.MethodsThe participants were 73,890 women in Nurses' Health Study (NHS; 1984–2016), 92,352 women in NHSII (1991–2017), and 43,266 men in Health Professionals Follow-Up Study (1986–2012) without cardiovascular disease and cancer at baseline. Plant-based diet quality was evaluated by the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Participants who reported that their meat and/or fish intakes were 0 or ResultsDuring the follow-up, 6,241 total stroke cases (including 3,015 ischemic and 853 hemorrhagic strokes) were documented. Compared to participants with the lowest PDIs, among participants with the highest PDIs, the hazard ratios (HRs) for total stroke were 0.94 (95% confidence interval 0.86–1.03) for PDI, 0.90 (0.83–0.98) for hPDI, and 1.05 (0.96–1.15) for uPDI. Participants in the highest hPDI showed marginally lower HR for ischemic stroke (0.92 [0.82–1.04]) and no consistent associations for hemorrhagic stroke. We observed no association between a vegetarian diet and total stroke (1.00 [0.76–1.32]), although the number of cases was small.ConclusionLower risk of total stroke was observed by those who adhered to a healthful plant-based diet.

Objectives Work engagement is defined as a positive, fulfilling feeling about one's job and is associated with higher productivity and morale. We performed a cross‐sectional study to investigate whether work engagement is related to healthier dietary behaviors among Japanese workers. Methods The present study was part of the Japanese Study of Health, Occupation, and Psychosocial Factors Related to Equity. A validated food frequency questionnaire was used to evaluate daily nutritional intake. The following seven nutrients were considered: salt intake, dietary fat (saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids), dietary fiber, folate, and isoflavone. Multivariable linear regression analysis was performed, adjusting for job stress, psychological distress, and other confounders. The baseline survey inquired about work engagement among 2,233 employees of 12 workplaces in Japan, representing a range of industries. Results The mean age of the sample was 43.4 ± 9.7 years and 89.7% of the participants were male. The mean score of work engagement was 2.9 ± 1.0. Higher work engagement was significantly positively associated with higher salt intake (β = 0.17, SE = 0.06, P = .006), monounsaturated fatty acids (β = 0.29, SE = 0.13, P = .03), polyunsaturated fatty acids (β = 0.28, SE = 0.09, P = .001), dietary fiber (β = 0.23, SE = 0.09, P = .012), and folate (β = 10.2, SE = 2.9, P = .005) consumption, but not saturated fatty acid (β = 0.16, SE = 0.11, P = .13) or isoflavone (β = 0.64, SE = 0.36, P = .072). Conclusion The present study suggested that higher work engagement is associated with a healthier pattern of dietary behaviors among workers. Improving work engagement may be a novel target for workplace health promotion.

OBJECTIVE We evaluated the associations between changes in plant-based diets and subsequent risk of type 2 diabetes. RESEARCH DESIGN AND METHODS We prospectively followed 76,530 women in the Nurses’ Health Study (NHS) (1986–2012), 81,569 women in NHS II (1991–2017), and 34,468 men in the Health Professionals Follow-up Study (1986–2016). Adherence to plant-based diets was assessed every 4 years with the overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs). We pooled results of the three cohorts using meta-analysis. RESULTS We documented 12,627 cases of type 2 diabetes during 2,955,350 person-years of follow-up. After adjustment for initial BMI and initial and 4-year changes in alcohol intake, smoking, physical activity, and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest decrease (>10%) in PDI and hPDI over 4 years had a 12–23% higher diabetes risk in the subsequent 4 years (pooled HR, PDI 1.12 [95% CI 1.05, 1.20], hPDI 1.23 [1.16, 1.31]). Each 10% increment in PDI and hPDI over 4 years was associated with a 7–9% lower risk (PDI 0.93 [0.91, 0.95], hPDI 0.91 [0.87, 0.95]). Changes in uPDI were not associated with diabetes risk. Weight changes accounted for 6.0–35.6% of the associations between changes in PDI and hPDI and diabetes risk. CONCLUSIONS Improving adherence to overall and healthful plant-based diets was associated with a lower risk of type 2 diabetes, whereas decreased adherence to such diets was associated with a higher risk.

IMPORTANCE: The 2015-2020 Dietary Guidelines for Americans recommend multiple healthy eating patterns. However, few studies have examined the associations of adherence to different dietary patterns with long-term risk of cardiovascular disease (CVD). OBJECTIVE: To examine the associations of dietary scores for 4 healthy eating patterns with risk of incident CVD. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of initially healthy women from the Nurses’ Health Study (NHS) (1984-2016) and the NHS II (1991-2017) and men from the Health Professionals Follow-up Study (HPFS) (1986-2012). The dates of analysis were July 25 to December 4, 2019. EXPOSURES: Healthy Eating Index–2015 (HEI-2015), Alternate Mediterranean Diet Score (AMED), Healthful Plant-Based Diet Index (HPDI), and Alternate Healthy Eating Index (AHEI). MAIN OUTCOMES AND MEASURES: Cardiovascular disease events, including fatal and nonfatal coronary heart disease (CHD) and stroke. RESULTS: The final study sample included 74 930 women in the NHS (mean [SD] baseline age, 50.2 [7.2] years), 90 864 women in the NHS II (mean [SD] baseline age, 36.1 [4.7] years), and 43 339 men in the HPFS (mean [SD] baseline age, 53.2 [9.6] years). During a total of 5 257 190 person-years of follow-up, 23 366 incident CVD cases were documented (18 092 CHD and 5687 stroke) (some individuals were diagnosed as having both CHD and stroke). Comparing the highest with the lowest quintiles, the pooled multivariable-adjusted hazard ratios (HRs) of CVD were 0.83 (95% CI, 0.79-0.86) for the HEI-2015, 0.83 (95% CI, 0.79-0.86) for the AMED, 0.86 (95% CI, 0.82-0.89) for the HPDI, and 0.79 (95% CI, 0.75-0.82) for the AHEI (P for trend

Few studies have evaluated the association between a healthful plant-based diet and health-related quality of life (HRQoL). We followed 50 290 women in the Nurses’ Health Study (NHS; 1992–2000) and 51 784 women in NHSII (1993–2001) for 8 years to investigate changes in plant-based diet quality in relation to changes in physical and mental HRQoL. Plant-based diet quality was assessed by three plant-based diet indices: overall plant-based diet index (PDI), healthful PDI (hPDI) and unhealthful PDI (uPDI). Physical and mental HRQoL were measured by physical component score (PCS) and mental component score (MCS) of the 36-Item Short Form Health Survey. Diet was assessed 2 years before the HRQoL measurements and both were updated every 4 years. The associations between 4-year changes in PDIs and HRQoL were evaluated. Each 10-point increase in PDI was associated with an improvement of 0·07 (95 % CI 0·01, 0·13) in PCS and 0·11 (95 % CI 0·05, 0·16) in MCS. A 10-point increase in hPDI was associated with an increment of 0·13 (95 % CI 0·08, 0·19) in PCS and 0·09 (95 % CI 0·03, 0·15) in MCS. Conversely, a 10-point increase in uPDI was associated with decreases in PCS and MCS (−0·07 (95 % CI −0·12, −0·02) and −0·10 (95 % CI −0·16, −0·05), respectively). Compared with a stable diet, an increase in hPDI was significantly associated with improvements in physical HRQoL in older women and with mental HRQoL in younger women. In conclusion, adherence to a healthful plant-based diet was modestly associated with improvements in both physical and mental dimensions of HRQoL.

OBJECTIVES: Puerto Ricans are the second-largest Hispanic sub-group and have high rates of type 2 diabetes (T2D). Yet, there is limited understanding of the molecular pathways that contribute to cardiometabolic risk in this high-risk group. We hypothesized that circulating gut microbiota metabolites, which have been linked to T2D risk in non-Hispanic whites, are associated with a higher T2D likelihood and cardiometabolic risk markers among older Puerto Ricans. METHODS: We developed a case-control study within the Boston Puerto Rican Health Study (BPRHS) with 275 prevalent T2D cases and 275 age and sex matched controls (mean age = 58.1 y, 71% female). We used LC/MS to measure baseline plasma gut microbiota metabolites (L-carnitine, betaine, choline, trimethylamine oxide [TMAO], and betaine: choline). We used conditional logistic regression to model the likelihood of prevalent T2D for each standard deviation (SD) increase in metabolites. Among controls free of T2D, we examined cross-sectional and prospective (2-year) linear associations (β [SD]) between metabolites and glycemia and dyslipidemia measures. RESULTS: After multivariable adjustment, significant differences in T2D likelihood [OR (95% CI)] were observed for each SD increase in L-carnitine [0.78 (0.62–0.99)], choline [1.33 (1.05–1.68)], betaine: choline [0.69 (0.54–0.88)], and TMAO [1.32 (1.04–1.67)]. We replicated findings for L-carnitine and betaine: choline in the WHI metabolomics study. Among BPRHS controls, cross-sectionally, higher betaine was associated with lower HOMA-IR (−9.97 [3.02]), insulin (−9.78 [2.83]), triglycerides (−11.4 [2.54]), and higher HDL-C (2.05 [0.65]). Prospectively, higher betaine and betaine: choline were associated with lower HOMA-IR (betaine −11.5 [3.63], betaine: choline −9.57 [3.68]), insulin (betaine −9.21 [3.27], betaine: choline −8.01 [3.31]), and glucose (betaine −2.17 [0.74], betaine: choline −1.58 [0.76]) concentrations, while higher choline was prospectively associated with higher triglycerides (5.17 [2.09]). No associations were seen between L-carnitine, TMAO, and cardiometabolic markers among controls. CONCLUSIONS: Plasma betaine, choline, and betaine: choline may be markers of cardiometabolic risk in this high-risk population. Future research should examine dietary and lifestyle correlates of betaine and choline. FUNDING SOURCES: NIH.

OBJECTIVES: Plant-based diets may lower type 2 diabetes (T2D) risk. Whether changes in adherence to plant-based diets are associated with subsequent T2D risk remains unknown. We aimed to evaluate the associations between 4 year changes in plant based diets and subsequent 4 year risk of T2D. METHODS: We prospectively followed 76,530 women in the Nurses’ Health Study (NHS, 1986–2012), 81,586 women in NHS II (1991–2017), and 34,468 men in the Health Professionals’ Follow-up Study (1986–2016). Diet was assessed every 4 years using validated food-frequency questionnaires. Adherence to plant-based diets was assessed using previously developed indices – the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Self reported T2D cases were validated by supplementary questionnaires. We used multivariable time dependent Cox proportional hazards models to estimate hazard ratios (HR) and 95% CIs for T2D associated with 4 year changes in adherence to plant based diets. Results of the three cohorts were pooled using an inverse variance-weighted meta-analysis. RESULTS: We documented 12,016 cases of T2D during 2818,485 person-years of follow-up. After adjustment for initial BMI, initial and 4-year changes in lifestyle and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest 4-year decrease (>10%) in PDI and hPDI had a 12%-23% higher T2D risk in the subsequent 4 years (HR for PDI, 1.12 (95% CI 1.05, 1.20), HR for hPDI, 1.23 (1.16, 1.31)). Conversely, each 10% incremental increase in PDI and hPDI over 4 years was associated with a 7%–9% lower T2D risk in subsequent 4 years (HR for PDI, 0.93 (0.90, 0.95), HR for hPDI, 0.91 (0.87, 0.95)). Changes in uPDI were not associated with T2D risk. Further adjustment for concurrent changes in body weight, a potential mediator, modestly attenuated the associations but results remained significant. We estimated that body weight changes explained 6.0%–36% of the associations between 4 year changes in PDI and hPDI and subsequent T2D risk. CONCLUSIONS: Improving adherence to overall and healthful plant based diets over a 4 year period was associated with a lower T2D risk, whereas decreased adherence to overall and healthful plant based diets was associated with a higher T2D risk. FUNDING SOURCES: Nutricia Research Foundation/NIH.

Objectives: To investigate the association between a plant-based diet index and microbial composition and functionality, as well as the inter-relationships between plant-based diets, gut microbiome, and cardiometabolic risk markers. Design and method: Metagenomic profiling was performed on 916 fecal samples collected among 301 men who participated in the Men’s Lifestyle Validation Study. Using data from a food frequency questionnaire, a Plant-based Diet Index (PDI) was derived to assess the adherence to a plant-based diets. The associations between PDI adherence and the relative abundance of microbial species and pathways were evaluated using Multivariate Association with Linear Models (MaAsLin2). P values below 0.25 after false discovery rate correction following the Benjamini-Hochberg method were considered statistically significant. Results: After multivariate adjustment, the value of the PDI score was significantly and positively associated with the ratio of Firmicutes to Bacteroidetes (Spearman r=0.10, P=0.005). Specifically, the PDI was significantly associated with the relative abundance of 77 taxa (including 39 species) out of 506 filtered taxa and 15 pathways (out of 80 filtered features). In particular, a higher adherence to the PDI was significantly, positively, associated with of the relative abundance of Firmicutes and of pathways involving degradation of complex plant carbohydrates. It was also inversely associated with the relative abundance of Bacteroidetes and Proteobacteria, as well as pathways involved in the urea cycle and amino acid biosynthesis. We also found that 14 species significantly interacted with PDI in modulating plasma ratio of TG to HDL-C. The association of PDI with lower TG to HDL ratio was significantly strengthened in the presence of the species positively correlated with the PDI score, such as Ruminococcus lactaris , Haemophilus parainfluenzae, and Methanobrevibacter smithii or in the absence of the species inversely correlated with the PDI score, such as Paraprevotella spp. Conclusions: A greater adherence to a plant-based diet was associated with a microbial profile featured by higher abundance of species in Firmicutes and depletion of species in Bacteroidetes and Proteobacteria, and such a profile may further strengthen the favorable associations between plant-based diets and human cardiometabolic risk.

Various oral glucose-lowering agents are available in Japan. Although the objective characteristics of these drugs are well described, little is known about treatment satisfaction by patients using these agents. The aim of this study was to assess treatment satisfaction of diabetic patients visiting diabetes clinics using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and to determine the association of the DTSQ scores with various factors including oral glucose-lowering agents. The study subjects were 754 outpatients who had been treated with one or more oral glucose-lowering agents, but not insulin or glucagon-like peptide-1 receptor agonist. The collected data included the response to DTSQ as completed by the patients, various parameters pertaining diabetes treatment including adherence, motivation, life style, social support, complications and cost burden from the patients and attending physicians. The associations among satisfaction scores and various parameters were analyzed by multiple linear regression analysis. In all subjects, use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) were positively, and irregular diet time were negatively associated with satisfaction scores significantly as well as some factors which had been previously reported to be associated. Subgroup analysis showed that adherence to diet and use of SGLT2i were positively in obese (body mass index ≥25 kg/m2), and HbA1c and irregular work time were negatively in non-obese (

Aims/Introduction The present study was carried out to generate induced pluripotent stem cells (iPSCs) from patients with fulminant type 1 diabetes, and evaluate the cytokine-induced apoptotic reactions of β-like insulin-producing cells differentiated from the iPSCs. Materials and Methods iPSCs were generated from fibroblasts of patients with fulminant type 1 diabetes by inducing six reprogramming factors. Insulin-producing cells were differentiated from the iPSCs in vitro. The proportion of cleaved caspase-3-positive or terminal deoxynucleotidyl transferase 2′-deoxyuridine, 5′-triphosphate nick end labeling-positive cells among insulin (INS)-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines was evaluated under treatment with tumor necrosis factor-α, interleukin-1β and interferon-γ. Ribonucleic acid sequencing was carried out to compare gene expressions in INS-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines. Results Two iPSC clones were established from each of three patients with fulminant type 1 diabetes. The differentiation of insulin-producing cells from fulminant type 1 diabetes iPSC was confirmed by immunofluorescence analysis and KCl-induced C-peptide secretion. After treatment with pro-inflammatory cytokines, these INS-positive cells showed higher expression of cleaved caspase-3 than those derived from control human iPSCs. Altered expression levels of several apoptosis-related genes were observed in INS-positive cells derived from the fulminant type 1 diabetes iPSCs by ribonucleic acid sequencing. Conclusions We generated iPSCs from patients with fulminant type 1 diabetes and differentiated them into insulin-producing cells. This in vitro disease model can be used to elucidate the disease mechanisms of fulminant type 1 diabetes.

OBJECTIVE This study aimed to investigate the prospective interrelationships among biomarkers that may provide mechanistic insights into obesity-related diseases. METHODS A total of 850 women in the Nurses' Health Study II with two fasting blood measurements (1996-1999 and 2010-2011) of adiponectin, leptin, soluble leptin receptor, insulin, retinol-binding protein 4, high-sensitivity C-reactive protein (hsCRP), and interleukin-6 were included. Biomarker interrelationships were examined in the following three ways: (1) cross-sectional associations at baseline and follow-up, (2) longitudinal associations of concurrent biomarker changes, and (3) prospective associations of each baseline biomarker with other biomarker changes. RESULTS In cross-sectional analyses, most biomarkers were correlated after multivariable adjustment including BMI, with the strongest correlations observed between leptin and insulin and between hsCRP and interleukin-6. In longitudinal analyses, similar results were observed after multivariable adjustment including weight change. However, in prospective analyses, only three associations observed in cross-sectional and longitudinal analyses were consistently significant (P

Introduction: Plant-based diets have been associated with health benefits, including lower risk of type 2 diabetes (T2D) and coronary heart disease (CHD). However, the association between plant-based diets and mortality remains unclear as previous studies did not take into account the quality of plant-based foods. To overcome this limitation, we recently developed three plant-based diet indices—an overall plant-based diet index (PDI), a healthful plant-based diet index (hPDI), and an unhealthful plant-based diet index (uPDI, emphasizing processed carbohydrates and fats)—and reported that hPDI and uPDI were differentially associated with T2D and CHD. In this study, we investigate associations between long-term changes in plant-based diet indices and subsequent total and cause-specific mortality in the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Hypothesis: We hypothesized that improved plant-based diet quality is associated with lower total and cardiovascular disease (CVD) mortality. Method: We included 47,983 women, aged 63±7y (mean±SD) in the NHS and 25,737 men, aged 63±9y in the HPFS who had no history of CVD or cancer on or before 1998 (baseline). We used multivariable Cox proportional-hazards regression to assess the association between 12-y pre-baseline changes (1986-1998) in three plant-based diet indices and subsequent total and cause-specific mortality (1998-2014). We adjusted for age, race, initial corresponding plant-based diet index score, BMI, family history of diabetes, myocardial infarction, or cancer, history of hypertension, hypercholesterolemia, or T2D, medications, postmenopausal status and postmenopausal hormone use in women, initial and 12-y pre-baseline changes in weight and other lifestyle-related factors. Results: Compared with those participants whose diets remained relatively stable during the pre-baseline 12-year period, among participants with the greatest increase in plant-based diet indices, the pooled hazard ratio (95% confidence interval [CI]) for total mortality was 0.92 (95% CI, 0.87 to 0.97) for PDI, 0.90 (95% CI, 0.86 to 0.95) for hPDI, and 1.11 (95% CI, 1.05 to 1.16) for uPDI. For CVD-specific mortality, a 10-point increase in hPDI was associated with a 10% lower risk (95% CI, 5 to 15), while a 10-point increase in uPDI was associated with a 6% higher risk (95% CI, 0 to 12). We found no evidence for changes in plant-based diet indices and subsequent risk of cancer mortality. Conclusions: Improved plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of an unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

Type 1 diabetes is a disease characterized by destruction of the β-cells in the pancreatic islets. The inhibitory receptor programmed cell death-1 (PD-1) and its ligands, programmed cell death ligand-1 (PD-L1) and PD-L2, have been shown to play an important role in regulating T-cell activation and peripheral tolerance. Inhibitors targeting PD-1 or PD-L1 are especially advantageous in the treatment of cancer. There are several reports where type 1 diabetes developed after administration of anti–PD-1 antibody (1). However, there is no report containing an immunohistochemical study of the pancreas. At the age of 55 years, a male patient underwent left radical nephrectomy for kidney cancer. At age 60, he was diagnosed with type 2 diabetes. Under the administration of vildagliptin, his hemoglobin A1c was maintained at ∼6% (41 mmol/mol). He was diagnosed with gallbladder metastasis of renal carcinoma at age 61 and underwent a cholecystectomy. Thereafter, he was diagnosed with renal carcinoma pancreatic metastasis, which increased in size, whereupon anti–CTLA4 antibody (ipilimumab) and anti–PD-1 antibody (nivolumab) combination therapy was started. Ipilimumab and nivolumab were administered four times over 2 months and nine times over 5 months, respectively. At age 63, 5 months after the start of administration, he developed diabetic ketoacidosis, his serum C-peptide was 1.8 ng/mL at that time, and insulin treatment was started. Anti–glutamic acid decarboxylase, anti–IA-2, and anti-IAA antibodies were negative, and his HLA haplotype was DRB1\*11:01-DQB1\*03:01 and DRB1\*09:01-DQB1\*03:03 . Two weeks after hospitalization, his serum C-peptide was

OBJECTIVES: The aim of this study was to explore the metabolic profiles, including both named metabolites and unknown peaks detected in the metabolomics measurement, that are related to long-term vegetable, fruit, and fruit juice consumption. METHODS: The study population for exploration included 5270 participants and for replication included 4216 participants in the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study. Plasma metabolic profiling was conducted by liquid chromatography-tandem mass spectrometry. Long-term vegetable, fruit, and fruit juice consumption was estimated from food-frequency questionnaires. We included 332 named metabolites and 2561 unknown peaks in the exploration analysis. Partial Spearman correlation analyses were used to assess the associations of vegetable, fruit, and fruit juice consumption with individual metabolites. We further identified metabolic signatures using machine learning models. RESULTS: We observed a panel of named metabolites and unknown peaks that were significantly associated with long-term vegetable, fruit, and fruit juice consumption (P value 0.4) with fruit juice, especially orange juice consumption, relative to the named metabolites. Metabolic signatures, comprised of 78, 104, and 41 named metabolites, were robustly correlated with total vegetable, total fruit, and total fruit juice consumption, respectively (Pearson r = 0.27–0.37 between the signature and dietary consumption in exploration samples, and 0.24–0.27 in replication samples). Adding unknown peaks into the metabolic signature strengthened the Pearson r by 17.7% for total vegetable, 9.5% for total fruit, and 5.3% for total fruit juice consumption. CONCLUSIONS: Using plasma metabolomics platform, we identified metabolic profiles, including named metabolites and unknown peaks, that reflect long-term vegetable, fruit, and fruit juice consumption, respectively. FUNDING SOURCES: None.

Background A healthful plant-based diet is associated with lower risk of cardiometabolic diseases. However, it is still unclear whether such benefits are due to its favorable effects on adiposity-associated biomarkers. Objective We investigated the associations between biomarkers and 3 plant-based diet indices: an overall plant-based diet index (PDI); a healthful plant-based diet index (hPDI); and an unhealthful plant-based diet index (uPDI). Methods In the Nurses’ Health Study II, 831 women [baseline mean age: 45 y; body mass index (BMI, kg/m2): 24.6] were randomly selected from those who provided 2 blood samples in 1996–1999 and 2010–2011 to measure plasma concentrations of adiponectin, leptin, soluble leptin receptor (sOB-R), insulin, retinol-binding protein-4, high-sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6). Plant-based diet indices were derived from semiquantitative food frequency questionnaires assessed at each blood collection. Linear mixed models were used to evaluate cross-sectional associations, and general linear models were used to evaluate longitudinal associations. Results In cross-sectional analyses with multivariable adjustment including BMI, higher hPDI was associated with lower concentrations of leptin, insulin, and hsCRP, and higher adiponectin and sOB-R concentrations (biomarker differences per 10-point higher hPDI: −7.2%, −10.0%, −13.6%, 3.0%, and 1.9%, respectively; P ≤ 0.025). A higher uPDI was associated with higher concentrations of leptin and insulin (4.4% and 4.8%, respectively; P ≤ 0.048). In longitudinal analyses with multivariable adjustment including weight change, an increase in hPDI (improved plant-based diet quality) was inversely associated with changes in leptin and hsCRP (biomarker changes per 10-point hPDI increase: −7.7% and −17.8%, respectively; P ≤ 0.005), whereas an increase in uPDI (worsened plant-based diet quality) was positively associated with changes in leptin, hsCRP, and IL-6 (10.1%, 13.5%, and 12.4%, respectively; P ≤ 0.021). Conclusions Adherence to a healthful plant-based diet is associated with favorable long-term changes in adiposity-associated biomarker concentrations in women.

AIMS: We conducted a national survey to clarify the characteristics and clinical course of type 1 diabetes related to anti-programmed cell death-1 therapy. METHODS: We analyzed the detailed data of 22 patients that were collected using a Japan Diabetes Society survey and a literature database search. RESULTS: Among the 22 patients, 11 (50.0%) met the criteria for fulminant type 1 diabetes and 11 (50.0%) met the criteria for acute-onset type 1 diabetes. The average patient age was 63 years. The mean duration between the date of the first anti-PD-1 antibody injection and development of type 1 diabetes was 155 days and ranged from 13 to 504 days. Flu-like symptoms, abdominal symptoms, and drowsiness were observed in 27.8, 31.6, and 16.7% patients, respectively. Mean ± standard deviation or median (first quartile–third quartile) glucose levels, HbA1c levels, urinary C-peptide immunoreactivity levels, and fasting serum C-peptide immunoreactivity levels were 617 ± 248 mg/dl, 8.1 ± 1.3%, 4.1 (1.4–9.4) μg/day, and 0.46 (0.20–0.70) ng/ml, respectively. Seventeen of 20 patients (85.0%) developed ketosis, and 7 of 18 patients (38.9%) developed diabetic ketoacidosis. Ten of 19 patients (52.6%) showed at least one elevated pancreatic enzyme level at the onset and two of seven patients showed this elevation before diabetes onset. Only one of 21 patients was anti-glutamic acid decarboxylase antibody positive. CONCLUSIONS: Anti-programmed cell death-1 antibody-related type 1 diabetes varies from typical fulminant type 1 diabetes to acute-onset type 1 diabetes. However, diabetic ketoacidosis was frequently observed at the onset of diabetes. An appropriate diagnosis and treatment should be provided to avoid life-threatening metabolic alterations.

SummaryObjective Serum adiponectin levels are affected by gender, body fat mass, several pathological factors or therapeutic interventions and it might be also affected by age. This study aimed to investigate the relationship between serum adiponectin levels and age in several physiological states. Design, Patients and Measurements The study was carried out in 21 100 healthy subjects (12 363 men and 8737 women) and 1833 patients with type 2 diabetes (1233 men and 600 women). Physical and demographic characteristics were recorded, and blood samples were collected to measure serum adiponectin levels. Using these data, we determined the relationships between serum adiponectin levels and various parameters, including age. Results Serum adiponectin levels increased with increasing age of healthy subjects and in patients with diabetes, in both men and women. Serum adiponectin levels were positively correlated with age in healthy subjects and patients with diabetes, in both men and women. In stepwise multiple regression analysis with serum adiponectin levels as the dependent variable and physiological characteristics as explanatory variables, age was significantly and independently associated with serum adiponectin levels in each of these groups of subjects. Conclusions Serum adiponectin levels are significantly and positively associated with age in healthy subjects and in patients with diabetes. This association is independent of renal function, body fat status, glucose metabolism and lipid profiles.

To investigate the relationship between serum levels of cystatin C and adiponectin in patients with type 2 diabetes. We examined serum cystatin C and adiponectin levels in 234 patients with type 2 diabetes who visited our hospital. The serum level of cystatin C was positively correlated with age (P

A 27-year-old woman with severe proteinuria, diabetes mellitus, sensorineural hearing impairment, and slight renal dysfunction was admitted to our hospital. The patient was diagnosed as having mitochondrial kidney disease, a rare disease with mitochondrial 3243 A to G mutation. The patient’s mother and younger sister had the same mitochondrial mutation, with the younger sister also having proteinuria. Differing from general mitochondrial diabetic patients with decreased insulin secretion, this patient showed insulin resistance. The thickening of the carotid intima-media, high brachial ankle pulse wave velocity, and ischemic change in cerebral white matter implied progressive arteriosclerosis. The patient also had hypoadiponectinemia even though she only had a small amount of visceral fat, and this hypoadiponectinemia may be one of the reasons behind the insulin resistance and arteriosclerosis. This case showed that insulin resistance cannot be the sole reason to exclude the possibility of mitochondrial kidney disease, and also showed the potential relationship between mitochondrial mutation and hypoadiponectinemia.

A 66-year-old man with Cushing's syndrome due to adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) was treated for 7 years with trilostane, a 3β-hydroxysteroid dehydrogenase inhibitor. Administration of trilostane reduced the serum cortisol level to around the upper limit of normal for 7 years, and symptoms of excessive glucocorticoid production (such as moon face and obesity) were gradually improved. On the other hand, the size of both adrenal glands gradually increased despite treatment with trilostane. Though trilostane therapy could not prevent adrenal growth, it did suppress cortisol secretion over the long term, so it might be a reasonable option for AIMAH in addition to adrenalectomy.

The onset of fulminant type 1 diabetes mellitus is sometimes accompanied by sudden death or cardiac arrest. The aim of this study was to determine the risk factors for the development of these conditions at the onset of fulminant type 1 diabetes mellitus.We conducted a search of the literature on fulminant type 1 diabetes and sudden death or cardiac arrest published up to 2012 in PubMed and Ichushi (a Japanese article database), and a questionnaire survey was administered to the authors of the articles and to diabetes specialists affiliated to the Japan Diabetes Society. We analyzed the clinical data at disease onset of 17 patients with fulminant type 1 diabetes mellitus who experienced sudden death or cardiac arrest, and those of 257 patients who did not develop these conditions.Patients with sudden death or cardiac arrest were younger, had a higher rate of impaired consciousness, more severe acidosis, hyperglycemia, hyponatremia, hyperkalemia, and hypochloremia, a higher serum blood urea nitrogen level, a higher serum creatinine level, and a higher plasma osmolality level than the other patients. In multiple logistic regression analyses, plasma glucose level was positively associated with sudden death or cardiac arrest. Receiver operating characteristic curve analyses showed that patients with a plasma glucose level over 1000 mg/dl (55.5 mmol/l) were at a high risk of cardiac arrest.Severe metabolic derangement, especially a high plasma glucose level, is associated with sudden death or cardiac arrest at the onset of fulminant type 1 diabetes mellitus.

Aims Viral infection is associated with pancreatic beta cell destruction in fulminant type 1 diabetes mellitus. The aim of this study was to investigate the acceleration and protective mechanisms of beta cell destruction by establishing a model of viral infection in pancreatic beta cells. Methods Polyinosinic:polycytidylic acid was transfected into MIN6 cells and insulin-producing cells differentiated from human induced pluripotent stem cells via small molecule applications. Gene expression was analyzed by real-time PCR, and apoptosis was evaluated by caspase-3 activity and TUNEL staining. The anti-apoptotic effect of Exendin-4 was also evaluated. Results Polyinosinic:polycytidylic acid transfection led to elevated expression of the genes encoding IFNα, IFNβ, CXCL10, Fas, viral receptors, and IFN-inducible antiviral effectors in MIN6 cells. Exendin-4 treatment suppressed the elevated gene expression levels and reduced polyinosinic:polycytidylic acid-induced apoptosis both in MIN6 cells and in insulin-producing cells from human induced pluripotent stem cells. Glucagon-like peptide-1 receptor, protein kinase A, and phosphatidylinositol-3 kinase inhibitors counteracted the anti-apoptotic effect of Exendin-4. Conclusions Polyinosinic:polycytidylic acid transfection can mimic viral infection, and Exendin-4 exerted an anti-apoptotic effect both in MIN6 and insulin-producing cells from human induced pluripotent stem cells.

Objective: Along with the increasing prevalence of obesity and related diseases, particularly atherosclerotic diseases, metabolic syndrome (MetS) is now a common and major public health issue in many countries around the world. Adiponectin, a protein secreted by the adipose tissue, has become recognized as a key player in the development of MetS. These days, not only MetS but also borderline metabolic/physiological abnormalities, such as impaired fasting glucose, high normal blood pressure and high normal plasma cholesterol, have been reported to be risk factors for atherosclerotic disease. Therefore, we undertook this study to determine the relationship between adiponectin and borderline metabolic/physiological abnormalities, as well as MetS. Design: A cross-sectional study performed from April 2007 to November 2009. Subjects: In 16 892 Japanese adults (10 008 men and 6884 women), we examined the relationship between the serum adiponectin concentration and borderline metabolic/physiological abnormalities or MetS by a questionnaire survey about medical treatment, body size measurement and measurement of laboratory parameters including the serum adiponectin concentration. Results: Adiponectin showed a significant negative correlation with the number of MetS components. In subjects without overt diabetes mellitus, hypertension or dyslipidemia, the adiponectin concentration also showed a significant negative correlation with the number of borderline metabolic abnormalities. Conclusion: The decrease of circulating adiponectin may start before the development of diabetes mellitus, hypertension, dyslipidemia or MetS. Adiponectin is an important biomarker for reflecting the adverse influence of visceral fat in persons with MetS, and also in these subclinical states.