Tooth Discoloration in Patients With Neonatal Diabetes After Transfer Onto Glibenclamide: A previously unreported side effect

OBJECTIVE

To assess if tooth discoloration is a novel side effect of sulfonylurea therapy in patients with permanent neonatal diabetes due to mutations in KCNJ11.

RESEARCH DESIGN AND METHODS

A total of 67 patients with a known KCNJ11 mutation who had been successfully transferred from insulin injections onto oral sulfonylureas were contacted and asked about the development of tooth discoloration after transfer.

RESULTS

Altered tooth appearance was identified in 5 of the 67 patients. This was variable in severity, ranging from mild discoloration/staining (n = 4) to loss of enamel (n = 1) and was only seen in patients taking glibenclamide (glyburide).

CONCLUSIONS

These previously unreported side effects may relate to the developing tooth and/or to the high local concentrations in the children who frequently chewed glibenclamide tablets or took it as a concentrated solution. Given the multiple benefits of sulfonylurea treatment for patients with activating KCNJ11 mutations, this association warrants further investigation but should not preclude such treatment.Activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the ATP-sensitive potassium (K_ATP) channel, are the most common known cause of permanent neonatal diabetes (1,2). High-dose glibenclamide (glyburide) allows discontinuation of insulin and improves metabolic control in ∼90% of cases (2,3). Apart from transient diarrhea (4), no significant side effects have been reported. We report the development of tooth discoloration in five patients with a KCNJ11 mutation after successful transfer onto glibenclamide.     

Clinical and metabolic features of adult-onset diabetes caused by ABCC8 mutations

OBJECTIVE

Gain-of-function ABCC8/sulfonylurea (SU) receptor 1 mutations cause neonatal diabetes mellitus (NDM) or late-onset diabetes in adult relatives. Given the effectiveness of SU treatment in ABCC8-NDM patients, we further characterized late-onset ABCC8-associated diabetes.

RESEARCH DESIGN AND METHODS

Seven adult subjects from three NDM families and one family with type 2 diabetes were studied. Insulin secretion and insulin sensitivity were assessed using clamp techniques. We screened 139 type 2 diabetic patients who were well controlled by SU for ABCC8 mutations.

RESULTS

ABCC8 mutation carriers exhibited glucose intolerance, frank diabetes, or insulin-requiring diabetes since diagnosis. HbA_1c improved in five SU-treated patients. Insulin secretion capacity was impaired in three patients compared with adult control subjects but was restored after a 4-week SU trial in two patients. Cohort screening revealed four SU-treated patients with ABCC8 mutations, two of which are likely causal.

CONCLUSIONS

Although of rare occurrence, recognition of adult-onset ABCC8-associated diabetes may help in targeting patients for SU therapy.Activating ABCC8 mutations are responsible of neonatal diabetes mellitus (NDM) (1–5) and late-onset diabetes with variable clinical phenotypes (2,4,6,7). Sulfonylurea (SU) drugs bind the high-affinity pancreatic β-cell–expressed sulfonylurea receptor (SUR 1) (encoded by ABCC8) of the ATP-sensitive K⁺ channels (K_ATP channels) and close them, subsequently stimulating insulin secretion (8). SU treatment may successfully replace insulin to control diabetes during the neonatal period (2,9,10).Here, we report detailed clinical and metabolic investigations in seven adult carriers of gain-of-function ABCC8 mutations (2,7,11), of whom five developed late-onset diabetes diagnosed between the ages of 14 and 39 years. We also screened an adult outpatient cohort with type 2 diabetes well controlled by SU for ABCC8 mutations.     

Coincidence of a novel KCNJ11 missense variant R365H with a paternally inherited 6q24 duplication in a patient with transient neonatal diabetes

OBJECTIVE—Neonatal diabetes is a heterogeneous group of disorders with diabetes manifestation in the first 6 months of life. The most common etiology in permanent neonatal diabetes is mutations of the ATP-sensitive K⁺ channel subunits; in transient neonatal diabetes, chromosome 6q24 abnormalities are the most common cause.RESEARCH DESIGN AND METHODS—We report a sporadic case of diabetes without ketoacidosis diagnosed on the fourth day of life.RESULTS—Analysis of the KCNJ11 gene found a novel R365H mutation in the proband and her unaffected father. The functional analysis did not support pathogenicity of this variant. When the patient''s diabetes remitted in the seventh month of life, the 6q24 region was analyzed and a paternally inherited duplication was identified.CONCLUSIONS—Our case reports a coincidental novel KCNJ11 variant in a patient with transient neonatal diabetes due to a 6q24 duplication, illustrating the difficulty in testing neonates before the clinical course of neonatal diabetes is known.Neonatal diabetes is a heterogeneous group of disorders with diabetes manifestation before 6 months of life that most frequently has a monogenic etiology (1). In patients with permanent neonatal diabetes (i.e., without remission) (PND), mutations of the K_ATP channel subunits (encoded by the KCNJ11 and ABCC8 genes) and mutations of the insulin gene are the most common etiology (1). Transient neonatal diabetes (TND) usually resolves by 6 months of age, but more than 50% of TND patients relapse into diabetes during childhood or adulthood (2). Abnormalities of the imprinted region, 6q24, which encompasses the ZAC and HYMAI genes, cause ∼70% of TND cases (3). Mutations of K_ATP channel subunits are the second most common etiology (3).     

Double Heterozygous Mutations Involving Both HNF1A/MODY3 and HNF4A/MODY1 Genes: A case report

OBJECTIVE

We describe a maturity-onset diabetes of the young (MODY) case with mutations involving both HNF4A and HNF1A genes.

RESEARCH DESIGN AND METHODS

A male patient was diagnosed with diabetes at age 17; the metabolic control rapidly worsened to insulin requirement. At that time no relatives were known to be affected by diabetes, which was diagnosed years later in both the parents (father at age 50 years, mother at age 54 years) and the sister (at age 32 years, during pregnancy).

RESULTS

The genetic screening showed a double heterozygosity for the mutation p.E508K in the HNF1A/MODY3 gene and the novel variant p.R80Q in the HNF4A/MODY1 gene. The genetic testing of the family showed that the father carried the MODY3 mutation while the mother, the sister, and her two children carried the MODY1 mutation.

CONCLUSIONS

MODY1 and MODY3 mutations may interact by chance to give a more severe form of diabetes (younger age at presentation and early need of insulin therapy to control hyperglycemia).Maturity-onset diabetes of the young (MODY) (MIM #606391) is a genetically and clinically heterogeneous group of disorders characterized by early onset of noninsulin-dependent diabetes and autosomal dominant inheritance. At least seven types of MODY have been identified (1). Heterozygous mutations of the gene encoding the hepatocyte nuclear factor 1-α (HNF1A/MODY3) are the most common causes of MODY in northern Europe and a frequent cause of MODY in many other populations. Mutations in the HNF4α gene (HNF4A/MODY1) are considerably less common (2,3).We describe the clinical history of a family, including a case in which double heterozygosity for two MODY mutations was documented.     

Maturity-Onset Diabetes of the Young in Children With Incidental Hyperglycemia:: A multicenter Italian study of 172 families

OBJECTIVE

To investigate the prevalence of maturity-onset diabetes of the young (MODY) in Italian children with incidental hyperglycemia.

RESEARCH DESIGN AND METHODS

Among 748 subjects age 1–18 years with incidental hyperglycemia, minimal diagnostic criteria for MODY were met by 172 families. Mutational analyses of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes were performed.

RESULTS

We identified 85 GCK gene mutations in 109 probands and 10 HNF1Α mutations in 12 probands. In GCK patients, the median neonatal weight and age at the first evaluation were lower than those found in patients with HNF1A mutations. Median fasting plasma glucose and impaired fasting glucose/impaired glucose tolerance frequency after oral glucose tolerance testing were higher in GCK patients, who also showed a lower frequency of diabetes than HNF1A patients.

CONCLUSIONS

GCK mutations are the prevailing cause of MODY (63.4%) when the index case is recruited in Italian children with incidental hyperglycemia.Between 1992–1999, the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) Study Group on childhood pre-diabetes recruited 748 individuals with incidental hyperglycemia to be screened for markers of type 1 diabetes (1,2). Among autoantibody-negative subjects, a significant number (∼23%) met the criteria for clinical diagnosis of maturity-onset diabetes of the young (MODY), i.e., two or three consecutive generations with hyperglycemia diagnosed before age 25 years (3,4). Alterations in at least six different genes cause MODY (3), with mutations of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes accounting for up to 85% of MODY in Europe. Defects of other MODY genes are quite rare (3). The aim of this study was to screen for GCK and HNF1Α genes in 172 Italian children with incidental hyperglycemia and clinical diagnosis of MODY.     

Incidence of Bladder Cancer in Patients With Type 2 Diabetes Treated With Metformin or Sulfonylureas

OBJECTIVE

Previous studies evaluating the effect of metformin on cancer risk have been impacted by time-related biases. To avoid these biases, we examined the incidence of bladder cancer in new users of metformin and sulfonylureas (SUs).

RESEARCH DESIGN AND METHODS

This cohort study included 87,600 patients with type 2 diabetes in The Health Improvement Network database. Use of metformin or an SU was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared metformin use with SU use, adjusted for age, sex, smoking, obesity, and HbA_1c level.

RESULTS

We identified 196 incident bladder cancers in the metformin cohort and 66 cancers in the SU cohort. Use of metformin was not associated with decreased bladder cancer risk (HR 0.81 [95% CI 0.60–1.09]). This association did not differ by sex (P for interaction = 0.20). We observed no association with duration of metformin relative to SU use (3 to <4 years of use: 0.57 [0.25–1.34]; 4 to <5 years of use: 0.93 [0.30–2.85; ≥5 years of use: 1.18 [0.44–3.19]; P for trend = 0.26).

CONCLUSIONS

Use of metformin is not associated with a decreased incidence of bladder cancer. Similar methods should be used to study other cancers that have previously been identified as potentially preventable with metformin.     

Reduced Incidence of Lower-Extremity Amputations in People With Diabetes in Scotland: A nationwide study

OBJECTIVE

To establish the incidence of nontraumatic lower-extremity amputation (LEA) in people with diabetes in Scotland.

RESEARCH DESIGN AND METHODS

This cohort study linked national morbidity records and diabetes datasets to establish the number of people with diabetes who underwent nontraumatic major and minor LEA in Scotland from 2004 to 2008.

RESULTS

Two thousand three hundred eighty-two individuals with diabetes underwent a nontraumatic LEA between 2004 and 2008; 57.1% (n = 1,359) underwent major LEAs. The incidence of any LEA among persons with diabetes fell over the 5-year study period by 29.8% (3.04 per 1,000 in 2004 to 2.13 per 1,000 in 2008, P < 0.001). Major LEA rates decreased by 40.7% from 1.87 per 1,000 in 2004 to 1.11 per 1,000 in 2008 (P < 0.001).

CONCLUSIONS

There has been a significant reduction in the incidence of LEA in persons with diabetes in Scotland between 2004 and 2008, principally explained by a reduction in major amputation.Diabetes-related foot disease results in major morbidity and mortality (1). National and global amputation rates vary considerably (2,3) because of confounding factors, such as ethnicity, case definition, and ascertainment of diabetes prevalence (4).The aim of this study was to establish any change in the incidence of diabetes-related nontraumatic lower-extremity amputation (LEA) in Scotland from 2004 to 2008.     

Impact of Carbohydrate Counting on Glycemic Control in Children With Type 1 Diabetes

OBJECTIVE

To study the association between parent carbohydrate counting knowledge and glycemic control in youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

We assessed 67 youth ages 4–12 years with type 1 diabetes (duration ≥1 year). Parents estimated carbohydrate content of children''s meals in diet recalls. Ratios of parent estimates to computer analysis defined carbohydrate counting knowledge; the mean and SD of these ratios defined accuracy and precision, respectively. A1C defined glycemic control.

RESULTS

Greater accuracy and precision were associated with lower A1C in bivariate analyses (P < 0.05). In a multivariate analysis (R²= 0.25, P = 0.007) adjusting for child age, sex, and type 1 diabetes duration, precision (P = 0.02) and more frequent blood glucose monitoring (P = 0.04), but not accuracy (P = 0.9), were associated with lower A1C. A1C was 0.8% lower (95% CI −0.1 to −1.4) among youth whose parents demonstrated precision.

CONCLUSIONS

Precision with carbohydrate counting and increased blood glucose monitoring were associated with lower A1C in children with type 1 diabetes.Medical nutrition therapy in type 1 diabetes is associated with improved glycemic outcomes (1,2). Meal-planning strategies for type 1 diabetes emphasize the relationship between prandial insulin dose selection and the anticipated amount of carbohydrate to be consumed. Although no method for carbohydrate estimation has proven superior in the management of youth with type 1 diabetes, carbohydrate counting has become a principal strategy for children with type 1 diabetes (3,4). In this study, we investigated the association between parental carbohydrate counting knowledge and glycemic control in youth with type 1 diabetes.     

Polyendocrinopathy in Children, Adolescents, and Young Adults With Type 1 Diabetes: A multicenter analysis of 28,671 patients from the German/Austrian DPV-Wiss database

OBJECTIVE

To investigate diabetes-specific autoantibodies and additional autoimmune phenomena in a large cohort of young patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Data from 28,671 patients <30 years with type 1 diabetes from 242 specialized centers in Germany and Austria were analyzed.

RESULTS

At least one β-cell antibody was present in 81.6% of patients. β-cell–Ab-negative patients were significantly younger at diabetes onset (P < 0.0001). A total of 19.6% had positive thyroid antibodies with female predominance (62%, P < 0.0001). Antibodies to tissue transglutaminase were present in 10.7%, with a significantly longer duration of diabetes (P < 0.0001). Parietal cell antibodies were found in 283 patients, associated with older age (P < 0.001), and adrenal antibodies were present in 94 patients. In 575 patients, at least three different autoimmune phenomena were present.

CONCLUSIONS

Thyroid autoimmunity and antibodies suggestive for celiac disease are the most prevalent additional immune phenomena in type 1 diabetes. Parietal/adrenal antibodies are rare.Additional autoimmune phenomena such as Hashimoto thyroiditis or celiac disease are a frequent observation in type 1 diabetes (1,2). The appearance of autoantibodies is often the first detectable sign of autoimmune diseases (3). The aim of this study was to investigate screening frequency and prevalence of autoimmune phenomena in a large cohort of children, adolescents, and young adults with type 1 diabetes.     

Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing loss,retinitis pigmentosa,and hyperinsulinemic hypoglycemia ranging from severe to mild with conversion to diabetes

OBJECTIVE

To evaluate the phenotype of 15 children with congenital hyperinsulinism (CHI) and profound hearing loss, known as Homozygous 11p15-p14 Deletion syndrome (MIM #606528).

RESEARCH DESIGN AND METHODS

Prospective clinical follow-up and genetic analysis by direct sequencing, multiplex ligation-dependent probe amplification, and microsatellite markers.

RESULTS

Genetic testing identified the previous described homozygous deletion in 11p15, USH1C:c.(90+592)_ABCC8:c.(2694–528)del. Fourteen patients had severe CHI demanding near-total pancreatectomy. In one patient with mild, transient neonatal hypoglycemia and nonautoimmune diabetes at age 11 years, no additional mutations were found in HNF1A, HNF4A, GCK, INS, and INSR. Retinitis pigmentosa was found in two patients aged 9 and 13 years. No patients had enteropathy or renal tubular defects. Neuromotor development ranged from normal to severe delay with epilepsy.

CONCLUSIONS

The phenotype of Homozygous 11p15-p14 Deletion syndrome, or Usher-CHI syndrome, includes any severity of neonatal-onset CHI and severe, sensorineural hearing loss. Retinitis pigmentosa and nonautoimmune diabetes may occur in adolescence.Congenital hyperinsulinism (CHI, MIM #256450) is a heterogeneous disease with hyperinsulinemic hypoglycemia, most frequently caused by mutations in ABCC8 (1,2). Usher syndrome 1C (USH1C, MIM #296904) is caused by mutations in USH1C (3), a gene situated next to ABCC8 on chromosome 11p15.1. A very rare, homozygous contiguous gene deletion, including USHIC and ABCC8, has been described in three patients, characterized by severe CHI, deafness, vestibular hypofunction, severe enteropathy, and renal tubular dysfunction (MIM #606528) (4,5).We report on 15 new patients from eight consanguineous families with the same homozygous deletion, but with clinical heterogeneity and with manifestations from β-cells, inner ear, and retina only.     

Cardiovascular Autonomic Neuropathy, HDL Cholesterol, and Smoking Correlate With Arterial Stiffness Markers Determined 18 Years Later in Type 1 Diabetes

OBJECTIVE

To examine the relationship between cardiovascular autonomic neuropathy and pulse waveform analysis (PWA) measures of arterial stiffness in a childhood-onset type 1 diabetes population.

RESEARCH DESIGN AND METHODS

Cardiac autonomic nerve function was measured in the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes by heart rate variability (R-R interval) during deep breathing and expressed as expiration-to-inspiration (E/I) ratio. Other cardiovascular and diabetes factors were also assessed. PWA was performed using SphgymoCor Px on 144 participants at the 18-year follow-up examination. Univariate and multivariate analyses for associations between baseline nerve function and other cardiovascular and diabetes-related factors were performed for augmentation index (AIx), augmentation pressure (AP), and subendocardial viability ratio (SEVR), a surrogate marker of myocardial perfusion.

RESULTS

E/I ratio correlated negatively with both AIx (r = −0.18, P = 0.03) and AP (r = −0.32, P < 0.001) and positively with SEVR (r = 0.47, P < 0.001) univariately. Lower baseline E/I ratio, HDL cholesterol, and a history of smoking were associated with higher follow-up (18 years later) AIx and AP and lower SEVR in multivariate analyses. Higher baseline HbA₁ was also associated with higher AP and lower SEVR multivariately.

CONCLUSIONS

Cardiovascular autonomic neuropathy is associated with increased arterial stiffness measures and decreased estimated myocardial perfusion in those with type 1 diabetes some 18 years later. This association persists after adjustment for potential confounders as well as for baseline HbA₁, HDL cholesterol, and smoking history, which were also associated with these PWA measures.Cardiovascular disease occurs earlier and with greater frequency in people with diabetes, a finding particularly striking in women (1). These observations are especially true for young adults with type 1 diabetes, in whom coronary artery disease is increased 10-fold or greater (2). Much of the risk for coronary artery disease in type 1 diabetes lies in the presence and severity of atherosclerosis and its risk factors (dyslipidemia/hyperlipidemia). Blood flow dynamics and arteriosclerosis or arterial stiffening, which are measured in a variety of ways, are also important risk factors for cardiovascular events and mortality (3). Interestingly, in case-control studies, arterial stiffness indexes are shown to be increased generally in those with type 1 diabetes (4). Indexes of arterial stiffness can be measured noninvasively with pulse waveform analysis (PWA) using applanation tonometry (external application of a micromanometer-tipped probe over a peripheral artery) (5). PWA provides a variety of indexes and hemodynamic parameters, including 1) augmentation pressure (AP) and 2) augmentation index (AIx), both of which provide information about the effects of early wave reflection on central blood pressure, as well as 3) subendocardial viability ratio (SEVR), an indicator of potential for myocardial ischemia. SEVR is the ratio of the area under the time-pressure curve during diastole (an estimate of myocardial perfusion) to the area under the curve during systole (an estimate of cardiac workload) (6).Currently, few data are available concerning risk factors for increased arterial stiffness in those with type 1 diabetes. In addition to traditional cardiovascular disease risk factors, autonomic neuropathy (AN), a complication of type 1 diabetes, is of particular interest, as it predicts cardiovascular events and mortality (7). The autonomic nervous system is responsible for regulating heart rate and vascular tone and, therefore, may contribute to increased arterial stiffness in those with type 1 diabetes. Thus, the aim of the present study is to examine the association between cardiovascular autonomic nerve function and arterial stiffness, via AIx and AP, and myocardial perfusion, via SEVR, in a type 1 diabetic population.     

Extended Family History of Diabetes and Autoimmune Diseases in Children With and Without Type 1 Diabetes

OBJECTIVE

To determine the extended family history of diabetes or autoimmune diseases in families with and without children having type 1 diabetes.

RESEARCH DESIGN AND METHODS

Three hundred case families and 381 control families were interviewed using structured questionnaires.

RESULTS

The proportion of case children having at least one relative with type 1 diabetes outside the nuclear family was higher than that of control children (50.3 vs. 31.8%, P < 0.001). The proportions of case and control children having relatives with type 2 diabetes or gestational diabetes were similar. Other autoimmune diseases occurred more frequently among the case children (9.7 vs. 1.1%, P < 0.001), in the case nuclear families (22.0 vs. 12.9%, P = 0.002) and in relatives outside the case nuclear family (72.0 vs. 62.2%, P = 0.007).

CONCLUSIONS

Type 1 diabetes and autoimmune diseases not only cluster in the nuclear families of children with type 1 diabetes but are also overrepresented in their extended families.First degree relatives of patients with type 1 diabetes clearly have an increased disease risk (1–5), but little information is available about the occurrence of type 1 diabetes outside the nuclear family (6). It is also unclear whether type 2 diabetes and gestational diabetes are more frequently present in the families of children with type 1 diabetes (7–9). Type 1 diabetes is known to be associated with other autoimmune diseases, but there is a scarcity of data on the frequency of autoimmune diseases among other family members (10).     

Increasing prevalence of type 2 diabetes in Chinese adults in Shanghai

OBJECTIVE

Our objective was to determine the secular trend in prevalence of type 2 diabetes in Shanghai, China.

RESEARCH DESIGN AND METHODS

Two consecutive population-based surveys for type 2 diabetes were conducted in randomly selected adults aged 35–74 years in Shanghai in 2002–2003 (n = 12,329) and in 2009 (n = 7,423). Diagnosed type 2 diabetes was determined based on self-report, whereas those undiagnosed were identified by measured fasting and postload glucose according to 2009 American Diabetes Association criteria.

RESULTS

Age-standardized prevalence of diagnosed and undiagnosed type 2 diabetes increased from 5.1 and 4.6% in 2002–2003 to 7.4 and 5.2% in 2009. The prevalence of type 2 diabetes increased with age and was higher among men and in urban residents in both surveys (P < 0.001). Between the two surveys, the increase in the prevalence was more evident in the rural population (P < 0.001) and appeared more rapid in younger birth cohorts (P < 0.05).

CONCLUSIONS

Our results suggest that Shanghai has experienced an increasing burden of type 2 diabetes.Type 2 diabetes is a major global health problem that affects over 285 million individuals worldwide (1). Over past decades, a continuous increase in prevalence of type 2 diabetes, which parallels a marked lifestyle transition and a worldwide epidemic of obesity, has been observed in both developed and developing countries (2). Unlike the gradual transition in most Western countries, these changes in China have occurred over a very short time (3). This may have led to a more rapidly increasing burden of type 2 diabetes. In this study, we evaluated the trend of type 2 diabetes in Chinese adults using the data derived from two population-based surveys in Shanghai.     

Heart rate recovery after exercise is a predictor of silent myocardial ischemia in patients with type 2 diabetes

OBJECTIVE

Slow heart rate recovery (HRR) predicts all-cause mortality. This study investigated the relationship between silent myocardial ischemia (SMI) and HRR in type 2 diabetes.

RESEARCH DESIGN AND METHODS

The study enrolled 87 consecutive patients with type 2 diabetes and no chest symptoms. They underwent treadmill exercise testing and single-photon emission computed tomography imaging with thallium scintigraphy. Patients with abnormal myocardial perfusion images also underwent coronary angiography.

RESULTS

SMI was diagnosed in 41 patients (47%). The SMI group showed slower HRR than the non–SMI group (18 ± 6 vs. 30 ± 12 bpm; P < 0.0001). HRR was significantly associated with SMI (odds ratio 0.83 [95% CI 0.75–0.92]; P = 0.0006), even after adjustment for maximal exercise workload, resting heart rate, maximum heart rate, rate pressure product, HbA_1c, use of sulfonamides, and a history of cardiovascular disease.

CONCLUSIONS

HRR can predict SMI in patients with type 2 diabetes.Coronary artery disease (CAD) is the leading cause of death in patients with diabetes mellitus (1). Silent myocardial ischemia (SMI) is defined as myocardial ischemia without chest pain (2). It has been reported to occur in more than 20% of asymptomatic patients with type 2 diabetes (3), and early detection is extremely important.Recovery of the heart rate immediately after exercise is mediated by vagal reactivation (4), with slow heart rate recovery (HRR) being a predictor of all-cause mortality (5) and sudden death (6). The relationship between slow HRR and SMI in diabetes is unclear, so this study was performed to clarify the relationship in patients with type 2 diabetes.     

Gender difference in albuminuria and ischemic heart disease in type 2 diabetes

Objective

The value of urinary albumin excretion in the prediction of myocardial ischemia in men and women with type 2 diabetes is not well understood. We questioned whether gender influences the albuminuria-ischemic heart disease relationship in patients with type 2 diabetes.

Methods

We designed a matched case-control study of 926 patients with albuminuria (cases) and 926 age and body mass index matched patients without albuminuria (controls). Ischemic heart disease was defined as the presence of (1) history of angina pectoris or angina equivalent symptoms and critical care unit admission, (2) myocardial infarction and/or electrocardiographic evidence of Q-wave myocardial infarction, (3) coronary revascularization and/or stenting, (4) positive myocardial single-photon emission computed tomography scan, (5) ischemic ST-segment or T-wave changes, and (6) positive stress testing.

Results

Patients with albuminuria had a lower glomerular filtration rate and a longer diabetes duration than patients without albuminuria. In the group of cases, there were a greater number of men with ischemic heart disease (120 of 370; 32.4%) compared to women (97 of 559; 17.4%) (P<0.001). The odds ratio of having ischemic heart disease according to the presence or absence of albuminuria was 1.25 [95% CI: 1.01–1.56] (P<0.05) in all studied populations, 0.79 [95% CI: 0.51–1.21] (P=0.14) in women, and 2.84 [95% CI: 1.68–4.79] (P<0.001) in men. We showed that diabetes duration, high-density lipoprotein, low-density lipoprotein, and hemoglobin A_1c influence albuminuria in women, while diabetes duration, fasting blood sugar, and diastolic blood pressure influence albuminuria in men.

Conclusions

Men with albuminuria are at increased risk of ischemic heart disease compared to women. This may be related to the role of high-density lipoprotein on the albuminuria-gender relationship.     

Increased Density of Demodex folliculorum Mites in Pregnancies with Gestational Diabetes

Objective

To investigate the presence of Demodex in patients with gestational diabetes and the impact of glucose regulation on Demodex density in gestational diabetes.

Subjects and Methods

The study population consisted of 33 patients with gestational diabetes and 30 pregnant women without gestational diabetes (control group). The age, parity, gestational age, and BMI of the study group were recorded and the patients were divided into 2 groups, i.e. those with regulated and unregulated glucose levels, according to their postprandial 1st- and 2nd-hour glucose values. A standardized skin surface biopsy method was used to determine if patients had Demodex folliculorum infestation (>5 mites/cm² of skin).

Results

Patients with gestational diabetes had a statistically significantly higher Demodex density compared to the control group (24.2 vs. 3.3%; p < 0.001). Furthermore, a significantly higher proportion of gestational diabetes patients with unregulated glucose levels had a higher Demodex density compared to those in the regulated subgroup (6/19 vs. 2/14; p = 0.001).

Conclusion

Our study revealed that the Demodex density was increased in gestational diabetes patients. Further, poor glucose regulation could be the mechanism responsible for the increased Demodex density in gestational diabetes patients with unregulated glucose levels compared to those with regulated glucose levels.Key Words: Demodex folliculorum, Gestational diabetes, Pregnancy     

Age-Related Differences in the Frequency of Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents

OBJECTIVE

We studied the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in children in Finland.

RESEARCH DESIGN AND METHODS

From 2002 to 2005, data on virtually all children <15 years of age diagnosed with type 1 diabetes (n = 1,656) in Finland were collected.

RESULTS

DKA was present in 19.4% of the case subjects, and 4.3% had severe DKA. In children aged 0–4, 5–9, and 10–14 years, DKA was present in 16.5, 14.8, and 26.4%, respectively (P < 0.001). Severe DKA occurred in 3.7, 3.1, and 5.9%, respectively (P = 0.048). DKA was present in 30.1% and severe DKA in 7.8% of children aged <2 years.

CONCLUSION

The overall frequency of DKA in children is low in Finland at diagnosis of type 1 diabetes. However, both children <2 years of age and adolescents aged 10–14 years are at increased risk of DKA.The incidence of diabetic ketoacidosis (DKA) in children with newly diagnosed type 1 diabetes may be decreasing in developed countries (1,2).     

Effect of Type 1 Diabetes on Carotid Structure and Function in Adolescents and Young Adults: The SEARCH CVD study

OBJECTIVE

Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Participants with type 1 diabetes (N = 402) were matched to controls (N = 206) by age, sex, and race or ethnicity. Anthropometric and laboratory values, blood pressure, and IMT were measured. ANCOVA was used to assess differences controlling for demographic risk factors, cardiovascular risk factors, and HbA_1c.

RESULTS

Subjects were 18.9 ± 3.3 years old (50% male, 82.7% non-Hispanic white). Youth with type 1 diabetes had thicker bulb IMT, which remained significantly different after adjustment for demographics and cardiovascular risk factors. Age, sex, adiposity, and systolic blood pressure were consistent significant determinants of IMT. Adjustment for HbA_1c eliminated the difference, suggesting the difference was attributable to poor glycemic control.

CONCLUSIONS

Carotid IMT may be increased in youth with type 1 diabetes at high risk for cardiovascular disease. Better control of diabetes may be essential in preventing progression of atherosclerosis.Type 1 diabetes mellitus leads to increased carotid intima-media thickness (IMT) (1) and higher risk for cardiovascular disease later in life (2). Large studies of carotid ultrasound in youth with type 1 diabetes are lacking. We evaluated adolescents and young adults to determine if increased carotid IMT was present in subjects with type 1 diabetes.     

Diabetes differentially affects depression and self-rated health by age in the U.S

OBJECTIVE

To determine whether the relationship between age and physical and mental health varies by diabetes status in older U.S. adults.

RESEARCH DESIGN AND METHODS

Using data from the National Social Life, Health, and Aging Project, a national sample of 3,005 adults aged 57–85 years, we tested the significance of the interaction between age and diabetes in association with health states.

RESULTS

Respondents with diabetes in the youngest age cohort had more medical conditions than those without diabetes, a difference that narrowed with age (P for interaction <0.01). The youngest cohort with diabetes had a higher rate of depression compared to those without diabetes (14 vs. 8%). Depression declined with age and did not differ by diabetes status in the oldest respondents (P = 0.01 for age-diabetes interaction).

CONCLUSIONS

Diabetes differentially affects self-rated overall health and depression by age, with convergence in the oldest age-group with and without diabetes.Individualizing care of type 2 diabetes (1), particularly for older patients (2), has become a priority. Age influences the diabetes phenotype and therefore parameters guiding individualization of care. Earlier-onset type 2 diabetes is often more severe and insulin deficient (3,4), has a higher relative and absolute risk of mortality (5), and allows more time for complications to develop (6). Age also influences patient-specific illness perception. Older patients often have less diabetes-related distress than younger ones (7).Our goal in this report was to determine whether diabetes differentially impacts physical and mental health by age. We hypothesized that diabetes would have a greater impact on self-reported physical and mental health in middle age than in old age comparing persons with diabetes with those without diabetes within age cohorts.     

Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals

OBJECTIVE

We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes.

RESEARCH DESIGN AND METHODS

We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to β-cell function (β-GRS) and then assessing the association between each GRS and the clinical features.

RESULTS

Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 × 10⁻²¹). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = −0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = −0.032, SE = 0.0140, P = 0.022), and C-peptide index (β = −0.031, SE = 0.012, P = 0.0125).

CONCLUSIONS

Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell–preserving therapy.Type 2 diabetes affects nearly 300 million individuals worldwide, and its prevalence continues to increase in many countries, including Japan (1). Although the precise mechanisms underlying the development and progression of type 2 diabetes have not been elucidated, a combination of multiple genetic and/or environmental factors contribute to the pathogenesis of the disease (2,3). Impaired insulin secretion and insulin resistance, the two main pathophysiological mechanisms leading to type 2 diabetes, have a significant genetic component (4).Recent studies have confirmed ~40 genetic loci associated with type 2 diabetes (5); most of these loci were discovered in genome-wide association studies (6–16), with the exception of PPARG (17), KCNJ11 (18), and WFS1 (19), which were identified using candidate gene approaches, and TCF7L2, which was discovered using a linkage-positional cloning strategy (20). Among them, many loci (at least 10), such as MTNR1B, SLC30A8, THADA, TCF7L2, KCNQ1, CAMK1D, CDKAL1, IGF2BP2, HNF1B, and CENTD2, have been shown to be associated with impaired β-cell functions, whereas only a few loci such as PPARG, IRS1, and FTO have been associated with insulin resistance (13).Although the molecular mechanisms responsible for the susceptibility effect can be well assigned for some loci, such as those at KCNJ11 and SLC30A8, the mechanisms by which most genetic loci contribute to the development of type 2 diabetes are not understood.Recently, the construction of a genetic risk score (GRS) using information on these diabetes susceptibility loci has been shown to be useful for evaluating the risk of the development of type 2 diabetes in individuals (21–26). However, the currently available genetic information is obviously insufficient for predicting the development of type 2 diabetes, and little is known about the detailed relationship between the GRS and the clinical features of type 2 diabetes. In the current study, we selected 14 well-replicated and well-established genetic variants associated with type 2 diabetes in the Japanese population (25,27–32) and constructed a GRS, which may predict mechanism (β-cell function and insulin resistance) of diabetes development, to evaluate the possibility that currently available genetic information can be translated into clinical practice.