Masako Habu

Clinical characteristics of non-obese children with type 2 diabetes mellitus without involvement of β-cell autoimmunity.

AIMS We examined the clinical characteristics of non-obese Japanese children with type 2 diabetes mellitus (T2DM) not associated with β-cell autoimmunity. METHODS Of 218 children who were diagnosed as having T2DM by a school urine glucose screening program in Tokyo, 24 were identified as being non-obese and were enrolled in this study. None of the children had any evidence of β-cell autoimmunity or genetic disorders. RESULTS The mean ages at diagnosis and at the study were 12.5 ± 1.7 and 22.4 ± 5.7 years, respectively. Females were predominant (M/F ratio: 4/20). Family history of T2DM, mostly of the non-obese type, was present in 62.5% of the cases. In regard to the birth weight, 20.8% had a history of low birth weight, and 8.3% were large for gestational age. The mean fasting insulin level, HOMA-R, HOMA-β, and an insulinogenic index on the OGTT at the time of diagnosis were 11.8 ± 7.8 μU/ml, 5.4 ± 3.8, 96.1 ± 55.0 and 0.16 ± 0.14, respectively. Most patients were treated by either oral hypoglycemic drug (45.8%) or insulin (50.0%) therapy at the study, with the mean interval to the start of pharmacological treatment of 3.1 ± 2.3 years. CONCLUSIONS Non-obese children with T2DM seemed to show lower insulin secretory capacities with mild, but evident, insulin resistance even from the time of diagnosis, and also earlier requirement of pharmacological therapies during the clinical course. Some genetic factors not associated with autoimmunity may play a role in the etiology of T2DM in non-obese children.

Insulin resistance at diagnosis in Japanese children with type 2 diabetes mellitus

Background:  Insulin resistance at diagnosis was investigated in Japanese children with type 2 diabetes mellitus (T2DM).

Efficacy and safety of switching to insulin glulisine from other rapid-acting insulin analogs in children with type 1 diabetes.

We investigated the efficacy and safety of switching to insulin glulisine (GLU) from other rapid‐acting insulin analogs (Ra) in children with type 1 diabetes treated with multiple daily injections of insulin or continuous subcutaneous insulin infusion. A total of 26 children with type 1 diabetes were included. Ra in all of these patients was changed to GLU, and they were observed for a 6‐month period after having previously finished treatment with other Ra. The mean glycated hemoglobin value decreased from 7.6 ± 1.0 to 7.4 ± 0.9% (P = 0.0034), and mean plasma glucose values after breakfast and supper also improved from 183 ± 50 to 153 ± 32 mg/dL (P = 0.0035), and from 203 ± 29 to 164 ± 23 mg/dL (P < 0.0001), respectively. Furthermore, the mean frequency of hypoglycemia was reduced from 7 ± 6 to 4 ± 4/month (P = 0.0004), while insulin doses and obesity degree were stable with statistically non‐significant differences. In conclusion, switching to GLU might be a good treatment option for improving glycemic control in children with type 1 diabetes.

Basal insulin requirement of youth with type 1 diabetes differs according to age.

We investigated the percentage of total basal insulin dose to total daily insulin dose (%TBD) among Japanese youth of different ages with type 1 diabetes. The study enrolled 69 patients with type 1 diabetes who were treated with multiple daily injections of insulin. The participants were divided into the following age groups: group A, 0 to <10 years (n = 18); group B, 10 to <20 years (n = 31) and group C, 20 to <25 years (n = 20). We found no difference in the sex ratio, body mass index, and glycated hemoglobin and 2‐h postprandial C‐peptide levels among the three groups. Participants assigned to group B had a significantly higher percentage of total daily insulin dose than those in group A and group C (49.7 ± 10.4% vs 38.5 ± 13.7% and 38.3 ± 8.2%, P = 0.0005). In conclusion, the basal insulin requirements of Japanese youth with type 1 diabetes might have an age effect that is associated with puberty.

Diabetic ketoacidosis and severe hypoglycemia in management of type 1 diabetes during 2003–2013

Diabetic ketoacidosis (DKA) and severe hypoglycemia (SH) are the most serious problems encountered during the management of pediatric type 1 diabetes (T1D), but basal bolus therapy with multiple daily injections or continuous s.c. insulin infusion (CSII) have recently been shown to decrease the frequency of these acute complications. We investigated the frequency of DKA and SH, and their causes in the management of pediatric T1D during 2003–2013. DKA was defined as blood glucose >200 mg/dL, venous pH <7.3 or bicarbonate <15 mmol/L, with ketonemia and ketonuria. SH was defined as blood glucose <40 mg/dL, impaired consciousness and/or seizure, and inability to self-treat to raise blood glucose. The frequencies of DKA and SH during the study period were 0.019/patient/year and 0.041/ patient/year, respectively. The majority of patients with DKA had only one episode, while 31.3% of patients with SH experienced more than five episodes. The patients with DKA or SH had a significantly higher prevalence of microvascular complications (44.1% vs. 5.2%, P < 0.0001) and a higher prevalence of CSII treatment (44.1% vs. 30.9%, n.s.) than those without. A total of 31.9% of patients on CSII experienced either DKA or SH. Most patients with recurrent DKA or SH had psychosocial problems. The main causes of DKA were insulin omission, inadequate insulin injections and failure of sick-day management. Tubeand catheter-related problems, such as occlusion and winding, and accidental pull-out of catheters in CSII also frequently caused DKA. In contrast, the most common reason for SH was hypoglycemia unawareness due to autonomic neuropathy with increased duration of diabetes; with inadequate management of CSII when in a condition suggestive of hypoglycemia also being a common cause (Table 1). And compared to previous reports, the frequency of DKA and SH in pediatric patients with T1D has decreased in recent years. The popularization of basal bolus therapy using insulin analogues may have contributed to decreases in these two acute complications. In contrast, CSIIassociated adverse events, such as occlusion and winding of the tube and catheter, result in the interruption of insulin delivery and DKA can develop within a few hours. Moreover, inadequate management of CSII on a sick day can cause not only DKA but also SH. Unchanged basal infusion rates and bolus doses in CSII on a sick day with decreased appetite is a risk factor for SH. Therefore, patients treated with CSII and their families should receive education about how to cope with pump accidents and sick-day care. Measurement of ketone bodies at home in a case of excessive hyperglycemia is useful for detecting ketosis. Frequent self-monitoring of blood glucose, with special attention to overnight levels, should be encouraged to prevent the occurrence of SH, especially in patients with a tendency toward hypoglycemia unawareness. Moreover, for those with recurrent episodes of DKA or SH, the provision of psychological support for such patients and their families is important for preventing these acute complications.

Three years of liraglutide treatment offers continuously optimal glycemic control in a pediatric patient with maturity-onset diabetes of the young type 3

Abstract Sulfonylureas (SUs) are recommended as the first-line pharmacological treatment in patients with uncontrolled maturity-onset diabetes of the young type 3 (MODY3). In contrast, glucagon-like peptide-1 (GLP-1) receptor agonists have the advantages of a low risk of hypoglycemia and maintained β-cell function. We report a pediatric patient with MODY3 treated with a GLP-1 receptor agonist, liraglutide. A 12-year-old Japanese girl with MODY3 had been treated with insulin for 6 months since the time of diagnosis. After genetic analysis, we switched her treatment from insulin to liraglutide. After switching to liraglutide, the patient maintained optimal glycemic control with hemoglobin A1c levels of 6.8%–7.5% and had postprandial C-peptide levels >3.0 ng/mL during a 3-year treatment period. No adverse events associated with liraglutide were observed. GLP-1 receptor agonists are the potential medications for patients with MODY3 who maintain residual insulin secretion.

Pharmacologic treatment strategies in children with type 2 diabetes mellitus.

We treated 80 obese and 28 nonobese children diagnosed as having type 2 diabetes mellitus (T2DM). Among these patients, 26 obese and 23 nonobese children were assigned to pharmacologic therapies during the course of diabetes. Pharmacologic therapies were started if the HbA1c (NGSP) value exceeded 7.0% despite dietary and exercise management. For the 26 obese patients, metformin alone or in combination with an additional medication was frequently used. Only 2 patients independently received sulfonylureas (SUs) in the form of glimepiride. In addition, 9 patients were treated with basal insulin supported with oral hypoglycemic drugs (OHDs) or biphasic premix insulin. On the other hand, the 23 nonobese patients were frequently treated with insulin alone or in combination with an additional medication followed by SUs. The nonobese patients tended to require pharmacologic therapies, in particular insulin, at an earlier stage of diabetes as compared with the obese patients. New antidiabetic drugs, DPP-4 inhibitors and GLP-1 receptor agonists, seemed to exert positive effects on glycemic control without occurrence of hypoglycemic episodes in some patients regardless of the type of diabetes. These results suggest that pharmacologic treatment strategies in childhood T2DM should be tailored to individual patient characteristics.

Frequency of dawn phenomenon and its associations with age, HbA1c and diabetes duration in Japanese type 1 diabetes mellitus (T1DM) using the continuous glucose monitoring system (CGMS)

compared in terms of diabetes duration (13.0 ± 9.9 vs 10.0 ± 9.7: p<0.01)yr , HbA1c(8.3 ± 1.6 vs 8.5 ± 2.4: p<0.01)%, age at the time of the study (24.6 ± 18.0 vs 20.5 ± 14.9: p<0.01)yr. The subjects with dawn phenomenon had longer diabetes duration, lower HbA1c and were older. Furthermore, these subjects experienced hypoglycemia (< 70mg/dl) during the daytime. Conclusion The frequency of dawn phenomenon in the present study was lower than that in the previous studies .This might be attributable to there being many users of CSII amongour subjects and to Japanese foodscontaining a large amount of the carbohydrate as compared with protein. The associations of dawn phenomenon with longer diabetes duration and advanced age may be based on poor glycemic control. Furthermore, excess bolusescause hypoglycemia and low HbA1c.These results suggest that change in the basal insulin rate should be considered instead of an increase in the pre-meal bolus. We conclude that CGM should be used to adjust CSII.

Time to peak postprandial glucose levels in childhood-onset diabetic patients analyzed with a continuous glucose monitoring system.

The risks of complications due to chronic diabetes are indicated by an increase in average blood glucose levels and the range of blood glucose level fluctuation. Postprandial hyperglycemia should be the target of glycemic control in clinical practice. There are few studies on the time to peak postprandial glucose levels in children. Therefore, we investigated the time to peak in childhood-onset diabetic patients using a continuous glucose monitor system (CGMS). Twenty-seven patients with childhood-onset diabetes were included (male to female ratio, 9:18): 20 had type 1 diabetes, 3 had type 2 diabetes, and 4 had other types of diabetes. All patients underwent CGM on admission using the CGMS; their blood glucose levels were monitored up to 3 h after each meal. The time to peak postprandial blood glucose levels was retrospectively determined. The CGMS recorded the postprandial glucose levels 266 times. Average peak time of postprandial blood glucose and average blood glucose excursion were 96.3 ± 56.7 min and 86.5 ± 56.7 mg/dL, respectively. The average peak time and average blood glucose excursion were as follows: type 1 diabetes, 91.2 ± 56 min and 80.0 ± 62.3 mg/dL; type 2 diabetes, 92.7 ± 42.6 min and 105.8 ± 52.2 mg/dL; other types of diabetes, 112.1 ± 50.7 min and 82.8 ± 42.7 mg/dL. The average peak time and blood glucose excursion for meals were as follows: breakfast, 108.4 ± 53.7 min and 92.6 ± 60.6 mg/dL; lunch, 93.2 ± 51.8 min and 83.4 ± 48.6 mg/dL; and dinner, 88.3 ± 54.0 min and 83.9 ± 60.0 mg/dL. There was no correlation between time to peak postprandial blood glucose and HbA1c levels. The average time to peak postprandial blood glucose levels was approximately 90 min in both type 1 and 2 diabetes patients. The time to peak postprandial blood glucose levels reported here was delayed as compared to other studies on Japanese healthy adults with childhood-onset diabetes. The time to peak postprandial blood glucose levels in childhood-onset diabetic patients was approximately 90 min. As an indicator of glycemic control in childhood-onset diabetic patients, the CGMS was considered useful for determining the postprandial blood glucose levels in clinical practice.