Jencia Wong

Long-Term Complications and Mortality in Young-Onset Diabetes: Type 2 diabetes is more hazardous and lethal than type 1 diabetes

OBJECTIVE To evaluate long-term clinical outcomes and survival in young-onset type 2 diabetes (T2DM) compared with type 1 diabetes (T1DM) with a similar age of onset. RESEARCH DESIGN AND METHODS Records from the Royal Prince Alfred Hospital Diabetes Clinical Database, established in 1986, were matched with the Australian National Death Index to establish mortality outcomes for all subjects until June 2011. Clinical and mortality outcomes in 354 patients with T2DM, age of onset between 15 and 30 years (T2DM15–30), were compared with T1DM in several ways but primarily with 470 patients with T1DM with a similar age of onset (T1DM15–30) to minimize the confounding effect of age on outcome. RESULTS For a median observation period of 21.4 (interquartile range 14–30.7) and 23.4 (15.7–32.4) years for the T2DM and T1DM cohorts, respectively, 71 of 824 patients (8.6%) died. A significant mortality excess was noted in T2DM15–30 (11 vs. 6.8%, P = 0.03), with an increased hazard for death (hazard ratio 2.0 [95% CI 1.2–3.2], P = 0.003). Death for T2DM15–30 occurred after a significantly shorter disease duration (26.9 [18.1–36.0] vs. 36.5 [24.4–45.4] years, P = 0.01) and at a relatively young age. There were more cardiovascular deaths in T2DM15–30 (50 vs. 30%, P < 0.05). Despite equivalent glycemic control and shorter disease duration, the prevalence of albuminuria and less favorable cardiovascular risk factors were greater in the T2DM15–30 cohort, even soon after diabetes onset. Neuropathy scores and macrovascular complications were also increased in T2DM15–30 (P < 0.0001). CONCLUSIONS Young-onset T2DM is the more lethal phenotype of diabetes and is associated with a greater mortality, more diabetes complications, and unfavorable cardiovascular disease risk factors when compared with T1DM.

Timing Is Everything: Age of Onset Influences Long-Term Retinopathy Risk in Type 2 Diabetes, Independent of Traditional Risk Factors

OBJECTIVE—To test the hypothesis that age of type 2 diabetes onset influences inherent susceptibility to diabetic retinopathy, independent of disease duration and degree of hyperglycemia. RESEARCH DESIGN AND METHODS—Retinopathy data from 624 patients with a type 2 diabetes duration of 20–30 years (group A) were analyzed by stratifying patients according to age of onset of diabetes and glycemic control. Retinopathy status was scored clinically as per a modified Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. To obviate possible bias due to a higher attrition from comorbidities in those with later-onset diabetes and retinopathy, 852 patients with type 2 diabetes of shorter duration (10–12 years, group B) were similarly studied. RESULTS—Prevalence and severity of retinopathy was significantly higher in the younger-onset, group A patients. When further stratified according to mean A1C, retinopathy risk remained increased in younger-onset patients. The greatest impact was seen in those with a mean A1C >9% (odds ratio [OR] for retinopathy 16.6, 7.5, and 2.7 for age of diagnosis <45, 45–55, and >55 years, respectively, P = 0.003). By logistic regression, earlier type 2 diabetes onset is associated with increased retinopathy risk, independent of traditional risk factors (OR of retinopathy 1.9, 1.1, and 1 for age of onset <45, 45–55, and >55 years, respectively). Similar results were found in group B patients. CONCLUSIONS— These data suggest an increased inherent susceptibility to diabetic retinopathy with earlier-onset type 2 diabetes. This further supports the importance of delaying development of diabetes and also implies a need for more stringent metabolic targets for younger individuals.

An Inverse Relationship Between Age of Type 2 Diabetes Onset and Complication Risk and Mortality: The Impact of Youth-Onset Type 2 Diabetes

OBJECTIVE This study compared the prevalence of complications in 354 patients with T2DM diagnosed between 15 and 30 years of age (T2DM15–30) with that in a duration-matched cohort of 1,062 patients diagnosed between 40 and 50 years (T2DM40–50). It also examined standardized mortality ratios (SMRs) according to diabetes age of onset in 15,238 patients covering a wider age-of-onset range. RESEARCH DESIGN AND METHODS Complication status was assessed according to a standard protocol and extracted from our electronic database. Survival status was ascertained by data linkage with the Australian National Death Index. SMRs were calculated in comparison with the background Australian population and analyzed according to age of onset. RESULTS After matching for duration, despite their younger age, T2DM15–30 had more severe albuminuria (P = 0.004) and neuropathy scores (P = 0.003). T2DM15–30 were as commonly affected by metabolic syndrome factors as T2DM40–50 but less frequently treated for hypertension and dyslipidemia (P < 0.0001). An inverse relationship between age of diabetes onset and SMR was seen, which was the highest for T2DM15–30 (3.4 [95% CI 2.7–4.2]). SMR plots adjusting for duration show that for those with T2DM15–30, SMR is the highest at any chronological age, with a peak SMR of more than 6 in early midlife. In contrast, mortality for older-onset groups approximates that of the background population. CONCLUSIONS The negative effect of diabetes on morbidity and mortality is greatest for those diagnosed at a young age compared with T2DM of usual onset. These results highlight the growing imperative to direct attention toward young-onset T2DM and for effective interventions to be applied before middle age.

Gestational Diabetes Mellitus in Early Pregnancy: Evidence for Poor Pregnancy Outcomes Despite Treatment.

OBJECTIVE Recent guidelines recommend testing at <24 weeks of gestation for maternal dysglycemia in “high-risk” women. Evidence to support the early identification and treatment of gestational diabetes mellitus (GDM) is, however, limited. We examined the prevalence, clinical characteristics, and pregnancy outcomes of high-risk women with GDM diagnosed at <24 weeks of gestation (early GDM) and those with pre-existing diabetes compared with GDM diagnosed at ≥24 weeks of gestation, in a large treated multiethnic cohort. RESEARCH DESIGN AND METHODS Outcomes from 4,873 women attending a university hospital antenatal diabetes clinic between 1991 and 2011 were examined. All were treated to standardized glycemic targets. Women were stratified as pre-existing diabetes (n = 65) or GDM diagnosed at <12 weeks of gestation (n = 68), at 12–23 weeks of gestation (n = 1,247), or at ≥24 weeks of gestation (n = 3,493). RESULTS Hypertensive disorders in pregnancy including pre-eclampsia, preterm delivery, cesarean section, and neonatal jaundice (all P < 0.001) were more prevalent in women with pre-existing diabetes and early GDM. Macrosomia (21.8% vs. 20.3%, P = 0.8), large for gestational age (39.6% vs. 32.8%, P = 0.4), and neonatal intensive care admission (38.5% vs. 39.7%, P = 0.9) in women in whom GDM was diagnosed at <12 weeks of gestation were comparable to rates seen in women with pre-existing diabetes. CONCLUSIONS Despite early testing and current best practice treatment, early GDM in high-risk women remains associated with poorer pregnancy outcomes. Outcomes for those in whom GDM was diagnosed at <12 weeks of gestation approximated those seen in pre-existing diabetes. These findings indicate the need for further studies to establish the efficacy of alternative management approaches to improve outcomes in these high-risk pregnancies.

Hypovitaminosis D in Chinese type 2 diabetes: Lack of impact on clinical metabolic status and biomarkers of cellular inflammation

Objective: Low vitamin D (25 OH vitamin D) is implicated in the development of diabetes and the metabolic syndrome. We examined whether hypovitaminosis D has a clinically significant impact on glycaemia, metabolic status and inflammatory markers in Chinese patients with established type 2 diabetes. Methods: Characteristics of 109 patients aged over 50 years were stratified by 25 OH vitamin D status. Patients identified as 25 OH vitamin D deficient (≤ 50 nmol/L) received cholecalciferol 2,000 IU daily for three months. Measurement of HbA1c, metabolic syndrome parameters, 25 OH vitamin D, calcium, phosphate, PTH, hsCRP and ferritin were taken at baseline and then 25 OH vitamin D, PTH, calcium, phosphate monthly for three months in those on replacement therapy. Results: Vitamin D deficiency was common, affecting 36% of patients. There was no impact of hypovitaminosis D on metabolic syndrome status, HbA1c or insulin use (p ≥ 0.4 for all) and no association between 25OHVitD and ferritin or hsCRP (p ≥ 0.3 for all). Neither BMI nor the metabolic syndrome affected the incremental rise in 25OHVitD levels during supplementation. Conclusion: There is no relationship between hypovitaminosis D and metabolic control or inflammatory markers in established type 2 diabetes.This suggests that at least in Chinese populations, the effect of low vitamin D is not clinically significant once diabetes is established. Future 25OHVitD intervention trials should therefore focus on prevention in pre-diabetes.

Can Common Clinical Parameters Be Used to Identify Patients Who Will Need Insulin Treatment in Gestational Diabetes Mellitus

OBJECTIVE To identify patients with gestational diabetes mellitus (GDM) who will need antenatal insulin treatment (AIT) by using a risk-prediction tool based on maternal clinical and biochemical characteristics at diagnosis. RESEARCH DESIGN AND METHODS Data from 3,009 women attending the Royal Prince Alfred Hospital GDM Clinic, Australia, between 1995 and 2010 were studied. A risk engine was developed from significant factors identified for AIT using a logistic regression model. RESULTS A total of 51% of GDM patients required AIT. Ethnicity, gestation at diagnosis, HbA1c, fasting and 60-min glucose at oral glucose tolerance test, BMI, and diabetes family history were significant independent determinants of AIT. Notably, only 9% of the attributable risk for AIT can be explained by the clinical factors studied. A modeled risk-scoring system was therefore a poor predictor of AIT. CONCLUSIONS Baseline maternal characteristics including HbA1c alone cannot predict the need for AIT in GDM. Lifestyle, compliance, or as yet unmeasured influences play a greater role in determining AIT.

Antenatal Diagnosis of Fetal Genotype Determines if Maternal Hyperglycemia Due to a Glucokinase Mutation Requires Treatment

OBJECTIVE In women with hyperglycemia due to heterozygous glucokinase (GCK) mutations, the fetal genotype determines its growth. If the fetus inherits the mutation, birth weight is normal when maternal hyperglycemia is not treated, whereas intensive treatment may adversely reduce fetal growth. However, fetal genotype is not usually known antenatally, making treatment decisions difficult. HISTORY AND EXAMINATION We report two women with gestational diabetes mellitus resulting from GCK mutations with hyperglycemia sufficient to merit treatment. INVESTIGATION In both women, DNA from chorionic villus sampling, performed after high-risk aneuploidy screening, showed the fetus had inherited the GCK mutation. Therefore, maternal hyperglycemia was not treated. Both offspring had a normal birth weight and no peripartum complications. CONCLUSIONS In pregnancies where the mother has hyperglycemia due to a GCK mutation, knowing the fetal GCK genotype guides the management of maternal hyperglycemia. Fetal genotyping should be performed when fetal DNA is available from invasive prenatal diagnostic testing.

Alterations in Monocyte CD16 in Association with Diabetes Complications

Monocytes express many cell surface markers indicative of their inflammatory and activation status. Whether these markers are affected by diabetes and its complications is not known and was investigated in this study. Blood was obtained from 22 nondiabetic and 43 diabetic subjects with a duration of diabetes >10 years, including 25 without and 18 with clinically significant complications. The number of CD45+CD14+ monocytes and the percentage expressing the proinflammatory marker CD16 were determined by flow cytometry. Other markers of monocyte activation and expression of chemokine receptors were also examined. The relationship between monocyte CD16 and clinical data, selected cytokines, and chemokines was also investigated. Diabetes had no effect on total white cell number but increased monocyte number. Diabetes also significantly decreased the number of CD16+ monocytes but only in those with diabetic complications. Other markers of monocyte activation status and chemokine receptors were not affected by diabetes or complications status. Diabetes induced plasma proinflammatory cytokines and they were lower in diabetic subjects with complications compared to those without complications. These results suggest that the circulating monocyte phenotype is altered by diabetic complications status. These changes may be causally related to and could potentially be used to predict susceptibility to diabetic complications.

Morbidity and mortality in young-onset type 2 diabetes in comparison to type 1 diabetes: where are we now?

Increasingly, we recognise that type 2 diabetes in youth is a disease with an aggressive time course and a significant complication risk. On the other hand, outcomes for youth with type 1 diabetes appear generally to be improving. With increasing numbers of both types of diabetes in youth, it is timely that a comparative perspective is offered to help clinicians prognosticate more appropriately. Contemporary comparative studies add a new perspective to a consistent story, that for youth-onset type 2 diabetes, the development and progression of cardio-renal complications are increased and the survival prognosis is significantly worse than for type 1 diabetes. Here, we review this mounting evidence, highlight the importance of metabolic syndrome factors in the excess risk and underscore that there remains a significant mortality gap for youth with either type of diabetes, to be addressed as a matter of urgency.

Identifying Glucokinase Monogenic Diabetes in a Multiethnic Gestational Diabetes Mellitus Cohort: New Pregnancy Screening Criteria and Utility of HbA1c.

OBJECTIVE Glucokinase monogenic diabetes (GCK–maturity-onset diabetes of the young [MODY]) should be differentiated from gestational diabetes mellitus (GDM) because management differs. New pregnancy-specific screening criteria (NSC) have been proposed to identify women who warrant GCK genetic testing. We tested NSC and HbA1c in a multiethnic GDM cohort and examined projected referrals for GCK testing. RESEARCH DESIGN AND METHODS Using a GDM database, 63 of 776 women had a postpartum oral glucose tolerance test suggestive of GCK-MODY. Of these 63 women, 31 agreed to undergo GCK testing. NSC accuracy and HbA1c were examined. Projected referrals were calculated by applying the NSC to a larger GDM database (n = 4,415). RESULTS Four of 31 women were confirmed as having GCK-MODY (prevalence ∼0.5–1/100 with GDM). The NSC identified all Anglo-Celtic women but did not identify one Indian woman. The NSC will refer 6.1% of GDM cases for GCK testing, with more Asian/Indian women referred despite lower disease prevalence. Antepartum HbA1c was not higher in those with GCK-MODY. CONCLUSIONS The NSC performed well in Anglo-Celtic women. Ethnic-specific criteria should be explored.