Yasumichi Mori

Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats.

Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor gamma (PPARgamma), which is expressed primarily in adipose tissues. To elucidate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (< 2,500 micron2) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000 micron2) by approximately 50%. In fact, the percentage of apoptotic nuclei was approximately 2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue than control. Concomitantly, troglitazone normalized the expression levels of TNF-alpha which were elevated by 2- and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARgamma. The increased number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF-alpha and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance.

A Subtype of Diabetes Mellitus Associated with a Mutation of Mitochondrial DNA

BACKGROUND Several families have been described in which a mutation of mitochondrial DNA, the substitution of guanine for adenine (A-->G) at position 3243 of leucine transfer RNA, is associated with diabetes mellitus and deafness. The prevalence, clinical features, and pathophysiology of diabetes with this mutation are largely undefined. METHODS We studied 55 patients with insulin-dependent diabetes mellitus (IDDM) and a family history of diabetes (group 1), 85 patients with IDDM and no family history of diabetes (group 2), 100 patients with non-insulin-dependent diabetes mellitus (NIDDM) and a family history of diabetes (group 3), and 5 patients with diabetes and deafness (group 4) for the mutation. We also studied the prevalence and characteristics of diabetes in 39 patients with a syndrome consisting of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes who were known to have the mutation and 127 of their relatives (group 5). RESULTS We identified 16 unrelated patients with diabetes associated with the A-->G mutation: 3 patients from group 1 (6 percent), 2 patients from group 3 (2 percent), 3 patients from group 4 (60 percent), and 8 patients from group 5 (21 percent). We also identified 16 additional subjects who had diabetes and the mutation among 42 relatives of the patients with diabetes and the mutation in groups 1, 2, 3, and 4 and 20 affected subjects among the 127 relatives of the patients in group 5. Diabetes cosegregated with the mutation in a fashion consistent with maternal transmission, was frequently (in 61 percent of cases) associated with sensory hearing loss, and was generally accompanied by impaired insulin secretion. CONCLUSIONS Diabetes mellitus associated with the A-->G mutation at position 3243 of mitochondrial leucine transfer RNA represents a subtype of diabetes found in both patients with IDDM and patients with NIDDM in Japan.

Does the −11377 promoter variant of APM1 gene contribute to the genetic risk for Type 2 diabetes mellitus in Japanese families?

were also analysed for interaction with gender. This showed no difference between boys and girls (p=0.94). To our knowledge this is the first study indicating a gender difference in the impact of neonatal infections on the risk of Type 1 diabetes in children. The results are not likely to be caused by recall bias since all information is based on register data collected prior to diabetes onset and less than 1% of the patients have missing information. The analysis is based only on hospital records and since boys are more often hospitalised in the first year of life there could be a selection bias towards higher registration rate of infections in boys. However, if we assume that this higher registration rate is the same in diabetic and non-diabetic cases, this should not influence the results. The results might be explained by a gender difference in susceptibility to T cell-mediated autoimmune diabetes and gender difference in response to infections [5]. The observation of an interaction between gender and risk factors affecting the development of the immune regulatory system is of crucial relevance. Accordingly the effects of those risk factors should be taken into account in analyses where boys and girls are analysed together because of opposite effects in boys and girls. This result suggests that all studies on risk factors of autoimmune diabetes which possibly occur through an effect on the immune regulatory system have to be analysed separately for each gender or with interaction. This has implications for the evaluation of risk factors such as infections, vitamin D supplement and breastfeeding, especially when considering the impact of these risk factors in early childhood. J. Svensson, B. Carstensen, H. B. Mortensen, K. BorchJohnsen, the Danish Study Group of Diabetes in Childhood (DSBD) Steno Diabetes Centre, Gentofte, Denmark

Insulin Allergy and Immunologic Insulin Resistance Caused by Interleukin-6 in a Patient With Lung Cancer

Simultaneous occurrence of insulin allergy and immunologic insulin resistance has been reported in a few cases (1). A 62-year-old man with type 2 diabetes, who had been treated with insulin (premixed insulin of 30% aspart and 70% protaminated insulin aspart) for 3 months, noticed urticariform erythema and induration of the skin at the insulin-injection site. Erythema appeared immediately after the injection of insulin and disappeared after ∼20 min, while induration persisted for 3–4 days. HbA1c rose from 8.0 …

Impact of elevated serum lipoprotein (a) concentrations on the risk of coronary heart disease in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus is associated with a marked increase of coronary heart disease (CHD). We aimed to assess the impact of elevated serum lipoprotein (a) (Lp[a]) concentrations on the risk of CHD in patients with type 2 diabetes mellitus. A consecutive series of 352 outpatients was investigated. We determined the serum lipid profile and checked the patients for a history of CHD and of its traditional risk factors. Furthermore, the patients were divided into 3 groups according to the degree of elevation of the serum Lp(a) concentration: serum Lp(a) concentrations greater than 50 mg/dL, between 30 and 50 mg/dL, and less than 30 mg/dL, a presumed high normal value; and the prevalence of CHD was compared among the 3 groups. The serum Lp(a) concentrations in the subjects varied widely from 0.4 to 163.6 mg/dL. Patients with CHD had significantly higher serum Lp(a) concentrations than those without CHD (P = .0045). Logistic regression analysis to identify factors associated with the presence of CHD revealed that elevated serum Lp(a) is a significant risk factor (P = .0246). The prevalence of CHD increased with increasing serum Lp(a) concentrations (P = .048). Patients with serum Lp(a) concentrations greater than 50 mg/dL had a significantly higher prevalence of CHD than those with serum Lp(a) concentrations less than 30 mg/dL: the odds ratio of an elevated serum Lp(a) concentration was 3.346 (P = .039). In conclusion, elevated serum Lp(a) is a significant risk factor; and the risk of CHD appears to increase with increasing serum Lp(a) concentrations. Serum Lp(a) concentration of 50 mg/dL might represent a threshold level in relation to the risk of CHD in patients with type 2 diabetes mellitus.

Pancreatic ductal hyperplasia/dysplasia with obstructive chronic pancreatitis: an association with reduced pancreatic weight in type 1 diabetes

To the Editor: The report by Campbell-Thompson and colleagues [1], providing evidence that pancreatic weight is reduced irrespective of duration in type 1 diabetic donors, presented important characteristics of the pancreas in type 1 diabetes. We would like to offer two comments and introduce our own results.

Ketoacidosis as the initial clinical condition in nine patients with acromegaly: a review of 860 cases at a single institute

OBJECTIVE Excess GH causes insulin resistance and impaired glucose metabolism. The objective of this study was to clarify the prevalence of ketoacidosis as the initial presenting symptom of acromegaly. DESIGN AND METHODS Data were collected from 860 patients with acromegaly who underwent pituitary surgery at Toranomon Hospital over the last 32 years, between 1980 and 2011. RESULTS Nine cases had ketoacidosis before being diagnosed with acromegaly, including seven males and two females with a mean +/- S.D. age of 38.8 +/- 14.2 years. Serum GH and IGF1 levels were 155 +/- 203 ng/ml and 9.86 +/- 0.68 SDS before pituitary surgery and 3.6 +/- 1.7 ng/ml and 3.72 +/- 3.40 SDS after surgery respectively. The maximum tumor diameter was 28.2 +/- 11.6 mm (ranging from 15 to 47 mm, n=8). None of the patients were diagnosed with diabetes mellitus (DM) nor were they positive for antibodies related to type 1 DM. A possible precipitating factor for ketoacidosis in six cases was excessive ingestion of sugar-containing soft drinks. All the cases had invasive pituitary adenomas. After pituitary surgery, plasma glucose levels were under control without requiring insulin in all cases. Furthermore, six patients did not need oral hypoglycemic agents. CONCLUSIONS Approximately 1% of patients with acromegaly presented with diabetic ketoacidosis as their first clinical condition.

Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes‐resistant human leukocyte antigen DRB1*15:02 treated with nivolumab

Anti‐programmed cell death‐1 (PD‐1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute‐onset insulin‐dependent diabetes after anti‐PD‐1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti‐PD‐1 therapy. We describe an atypical case of hyperglycemia after anti‐PD‐1 antibody administration. A 68‐year‐old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA‐A*24:02 and ‐DRB1*09:01) and resistant (HLA‐DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti‐PD‐1 antibody‐induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case.

Effect of Sleep-Disordered Breathing on Albuminuria in 273 Patients With Type 2 Diabetes

STUDY OBJECTIVES Sleep-disordered breathing (SDB) can induce hyperglycemia, hypertension, and oxidative stress, conditions that are known to cause kidney damage. Therefore, SDB may exacerbate albuminuria, which is an established marker of early-stage kidney damage in patients with type 2 diabetes mellitus (T2DM). The association between SDB and albuminuria in patients with T2DM was investigated in this study. METHODS This cross-sectional study included 273 patients with T2DM who underwent portable sleep testing and measurement of urine albumin to creatinine ratio (UACR). The association between the severity of SDB and albuminuria was investigated. Patients were divided into three groups according to the respiratory event index (REI): the no or mild group (REI < 15 events/h), moderate (REI 15 to < 30 events/h), and severe (REI ≥ 30 events/h). Albuminuria was defined as UACR ≥ 3.4 mg/mmol creatinine. Logistic regression analysis for albuminuria included the categorical REI as the independent variable. RESULTS The median (interquartile range) REI of all patients (age 57.9 ± 11.9 years, mean ± standard deviation, male sex 81.7%, body mass index 26.7 [24.2-29.5] kg/m2, estimated glomerular filtration rate 82 [65-97] mL/min/1.73 m2) was 13.0 (7.0-24.2) events/h. The REI, as a categorical variable, was significantly associated with albuminuria after adjustment for other risk factors for albuminuria; REI 15 to < 30 events/h: odds ratio (OR) 3.35, 95% confidence interval (95% CI), 1.68-6.67, P < .001; REI ≥ 30: OR 8.52, 95% CI, 3.52-20.63, P < .001). In addition, the natural logarithm-transformed REI of all patients also correlated significantly with albuminuria. CONCLUSIONS The severity of SDB is associated with albuminuria in patients with T2DM.

A positive family history of hypertension might be associated with an accelerated onset of type 2 diabetes: Results from the National Center Diabetes Database (NCDD-02)

Type 2 diabetes, which is characterized by a combination of decreased insulin secretion and decreased insulin sensitivity, can be delayed or prevented by healthy lifestyle behaviors. Therefore, it is important that the population in general understands their personal risk at an early age to reduce their chances of ever developing the disease. A family history of hypertension is known to be associated with insulin resistance, but the effect of a family history of hypertension on the onset of type 2 diabetes has not well been examined. We performed a retrospective study examining patient age at the time of the diagnosis of type 2 diabetes by analyzing a dataset of 1,299 patients (1,021 men and 278 women) who had been diagnosed as having type 2 diabetes during a health checkup. The mean ± standard deviation of the patient age at the time of the diagnosis of diabetes was 49.1 ± 10.4 years for patients with a family history of hypertension and 51.8 ± 11.4 years for patients without a family history of hypertension (p < 0.001). A multivariate linear regression analysis showed a significant association between a family history of hypertension and a younger age at the time of the diagnosis of type 2 diabetes, independent of a family history of diabetes mellitus and a male sex, suggesting that a positive family history of hypertension might be associated with the accelerated onset of type 2 diabetes.