Aims
To compare large for gestational age (LGA) rates by maternal glucose levels in a real‐world setting with those in the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study. To examine the ...association between fasting plasma glucose (FPG), 1‐ and 2‐h on a 75‐g oral glucose tolerance tests (OGTT) and LGA.
Methods
Pregnancies were categorized according to HAPO thresholds. Category‐specific LGA rates were compared to those in HAPO. Categories with glucose thresholds below or above the diagnostic criteria for gestational diabetes mellitus (GDM) were labelled as lower and higher/GDM, respectively. GDM pregnancies were further stratified according to FPG or post‐load elevations and logistic regression was used to examine their independent association with LGA.
Findings
In our cohort of 97,032 pregnancies, rates of LGA increased with increasing maternal glucose in lower categories of FPG, 1‐ and 2‐h glucose (trend p < 0.01). However, LGA rates in higher/GDM categories were significantly lower in our study than those in HAPO for 1‐ and 2‐h glucose, but not for FPG. Elevated FPG alone was associated with an almost twofold increase in risk of LGA, while elevated post‐load glucose alone was associated with a 20% reduction in risk of LGA, compared to negative OGTT.
Conclusions
Real‐world data confirm the HAPO study findings at lower levels of maternal glycaemia. At higher levels, GDM diagnosis and treatment appear to be effective in reducing rates of LGA in pregnancies with post‐load glucose elevations, but not elevated FPG. Elevated FPG is a stronger predictor of LGA than post‐load glucose elevations.
Aims/hypothesis
This study aimed to examine the association of maternal diabetes, being large for gestational age (LGA) and breast-feeding with being overweight or obese in pre-school-aged children.
...Methods
Data on height and weight at the time of their pre-school (age 4–6 years) immunisation visit between January 2009 and August 2017, as well as breast-feeding status in the first 5 months of life, for 81,226 children born between January 2005 and August 2013 were linked with maternal hospitalisation and outpatient records and birth registry data. Children were grouped into six categories based on maternal diabetes status during pregnancy (no diabetes, gestational diabetes or pre-existing diabetes) and birthweight (appropriate for gestational age AGA or LGA). WHO criteria were used to identify children who were overweight or obese.
Results
There were 69,506 children in the no diabetes/AGA group (control), 5926 in the no diabetes/LGA group, 4563 in the gestational diabetes/AGA group, 573 in the gestational diabetes/LGA group, 480 in the pre-existing diabetes/AGA group and 178 in the pre-existing diabetes/LGA group. The rate of being overweight/obese at pre-school age ranged from 20.5% in the control group to 42.9% in the gestational diabetes/LGA group. The adjusted attributable risk per cent for LGA alone (39.4%) was significantly higher than that for maternal gestational diabetes (16.0%) or pre-existing diabetes alone (15.1%); the risk for the combinations of gestational diabetes/LGA and pre-existing diabetes/LGA were 50.1% and 39.1%, respectively. Further stratification of the pre-existing diabetes groups found the prevalence of being overweight/obese was 21.2% in the type 1/AGA group, 31.4% in the type 1/LGA group (similar to those in the no diabetes groups), 26.7% in the type 2/AGA group and 42.5% in the type 2/LGA group. Breast-feeding was associated with a lower likelihood of being overweight/obese in childhood in all groups except gestational diabetes/LGA and pre-existing diabetes/LGA (both type 1 and type 2).
Conclusion/interpretation
LGA is a stronger marker for risk of being overweight/obese in early childhood, compared with maternal diabetes during pregnancy. Rates of being overweight/obese in childhood were highest in LGA children born to mothers with gestational diabetes or pre-existing type 2 diabetes. Breast-feeding was associated with a lower risk of being overweight/obese in childhood in the majority of children; however, this association was not maintained in LGA children of mothers with diabetes.
Five-Year Follow-Up After Clinical Islet Transplantation
Edmond A. Ryan 1 ,
Breay W. Paty 1 ,
Peter A. Senior 1 ,
David Bigam 2 ,
Eman Alfadhli 1 ,
Norman M. Kneteman 2 ,
Jonathan R.T. Lakey 2 and
...A.M. James Shapiro 2
1 Department of Medicine, Clinical Islet Transplant Program, University of Alberta and Capital Health, Edmonton, Alberta, Canada
2 Department of Surgery, Clinical Islet Transplant Program, University of Alberta and Capital Health, Edmonton, Alberta, Canada
Address correspondence and reprint requests to Edmond A. Ryan, Clinical Islet Transplant Program, 2000 College Plaza, 8215
112th St., Edmonton, Alberta, Canada T6G 2C8. E-mail: edmond.ryan{at}ualberta.ca
Abstract
Islet transplantation can restore endogenous β-cell function to subjects with type 1 diabetes. Sixty-five patients received
an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 ± 1.2 years, their mean duration of diabetes
was 27.1 ± 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed
the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg
but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 ± 30,220
IE (11,910 ± 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants,
and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority (∼80%) have C-peptide
present post–islet transplant, but only a minority (∼10%) maintain insulin independence. The median duration of insulin independence
was 15 months (interquartile range 6.2–25.5). The HbA 1c (A1C) level was well controlled in those off insulin (6.4% 6.1–6.7) and in those back on insulin but C-peptide positive
(6.7% 5.9–7.5) and higher in those who lost all graft function (9.0% 6.7–9.3) ( P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required
half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 ±
0.06 vs. 0.76 ± 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed,
bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included
mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation
or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications
increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant.
There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve
glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up
to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further
progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing
toxic immunosuppression.
CBC, complete blood count
CMV, cytomegalovirus
HOMA, homeostasis model assessment
HYPO score, Hypoglycemic score
LI, lability index
LFT, liver function test
PRA, panel reactive antibody
Footnotes
Accepted April 13, 2005.
Received February 18, 2005.
DIABETES
Short-Term Intensive Insulin Therapy in Newly Diagnosed Type 2 Diabetes
Edmond A. Ryan , MD ,
Sharleen Imes , MSC and
Clarissa Wallace , MD
From the Department of Medicine, University of Alberta, ...Edmonton, Alberta, Canada
Address correspondence and reprint requests to Edmond A. Ryan, 362 Heritage Medical Research Bldg., University of Alberta,
Edmonton. Canada T6G 2S2. E-mail: edmond.ryan{at}ualberta.ca
Abstract
OBJECTIVE —Type 2 diabetes is associated with defects in insulin secretion and insulin action. Hyperglycemia may aggravate these defects,
a feature known as glucose toxicity. Previous studies have shown that acute correction of hyperglycemia in subjects with long-standing
type 2 diabetes gives only short-term improvement in glycemic control after discontinuation of insulin. The current study
attempts to identify any characteristics of patients with newly diagnosed type 2 diabetes (fasting glucose >11.0 mmol/l) who
would have a long-term benefit, in terms of glycemic control, from a brief course of insulin therapy.
RESEARCH DESIGN AND METHODS —A total of 16 subjects (52 ± 2 years old range 36–64, BMI 30.8 ± 1.9 kg/m 2 ) with newly diagnosed type 2 diabetes had a 2–3 week course of intensive insulin therapy that was then discontinued.
RESULTS —Fasting glucose fell from 13.3 ± 0.7 to 7.0 ± 0.4 mmol/l, and this improvement was maintained at the 1-year follow-up (6.7
± 0.3 mmol/l). The insulin area under the curve for the posttreatment oral glucose tolerance test also improved (8,251 ± 1,880
before therapy, 18,404 ± 4,040 directly after insulin therapy, and 42,368 ± 8,517 pmol · min at the 1-year follow-up). At
1 year, seven of the subjects maintained good glycemic control on diet therapy alone, eight required oral hypoglycemic agent
(OHA) therapy, and one required insulin therapy. The distinguishing features of those who did not require OHA or insulin therapy
were that they required less insulin during the active insulin therapy phase (0.37 ± 0.05 vs. 0.73 ± 0.07 units · kg −1 · day −1 ) and were able to attain a lower fasting serum glucose at the end of the period of insulin therapy (5.9 ± 0.3 vs. 7.7 ± 0.4
mmol/l).
CONCLUSIONS —These results demonstrate that in newly diagnosed type 2 diabetes with elevated fasting glucose levels, a 2- to 3-week course
of intensive insulin therapy can successfully lay a foundation for prolonged good glycemic control. The ease with which normoglycemia
is achieved on insulin may predict those patients who can later succeed in controlling glucose levels with attention to diet
alone.
AUC, area under the curve
OGTT, oral glucose tolerance test
OHA, oral hypoglycemic agent
Footnotes
C.W. has received honoraria from Lifescan Canada, Novo Nordisk, and Eli Lilly. E.A.R. has received honoraria from Eli Lilly.
Accepted February 2, 2004.
Received September 21, 2003.
DIABETES CARE
Summary box Clinical context-Mild gestational diabetes is associated with perinatal morbidity Diagnostic change-International recommendation to move from dual step testing to reliance on a single ...abnormal glucose value in an oral glucose tolerance test with reduced thresholds Rationale for change-An observational study showed that any degree of impaired glucose regulation in pregnancy is associated with adverse outcomes Leap of faith-Reducing mildly raised blood glucose concentrations will improve outcomes for mother and baby Effect on prevalence-Nearly 1 in 5 pregnancies will be identified as being affected by gestational diabetes: a 2-3-fold increase over existing levels of 2-6% Evidence of overdiagnosis-Despite increased diagnosis there is no evidence from randomised controlled clinical trials that outcomes are improved Harms from overdiagnosis-Many more women will experience medicalisation of their pregnancy with increased intervention Limitations-Maternal obesity and excess weight gain in pregnancy are associated with gestational diabetes; both affect birth weight and other more serious pregnancy outcomes. 6 Date Observations Recommended test Diagnostic criteria for oral glucose challenge test (mmol/L) Prevalence (%) Fasting blood glucose 1 hour 2 hour 3 hour 1930-40s Women who later developed (type 2) diabetes had high incidence of large babies and fetal loss Not yet developed - - - - NA 1950s The term "gestational diabetes" introduced for women with poor obstetric histories who during a subsequent pregnancy had high glucose levels on an OGTT OGTT 100 g in high risk patients - - > 9.4 - NA 1960s Women with high risk pregnancies followed postpartum with annual OGTT-a high proportion subsequently developed type 2 diabetes OGTT 100 g in high risk patients (need 2 abnormal values) >= 5.0 >= 9.2 >= 8.1 >= 6.9 2 Whole blood glucose levels 1979-80 Missed cases lead American Diabetes Association to recommend universal screening using criteria suggested by National Diabetes Data Group 50 g glucose challenge followed by OGTT 100 g (need 2 abnormal values) >= 5.8 >= 10.6 >= 9.2 >= 8.1 5 1990s Modification for using plasma not whole blood OGTT 100 g (need 2 abnormal values) >= 5.3 >= 10.0 >= 8.6 >= 7.8 6 2005-9 Randomised controlled trials in women with mild gestational diabetes identified by two step testing show modest benefit of treatment, predominantly on birth weight - - - - - - 2008-10 HAPO study shows continuous relation between untreated maternal blood glucose and some primary endpoints but no threshold for markedly increased risk OGTT 75 g, no screening and 1 abnormal value* >= 5.1 >= 10.0 >= 8.5 - 18 2013 Individual countries struggle to come up with guidelines for diagnosis. Diabetes diagnosed in early pregnancy at the first prenatal visit based on a fasting plasma glucose >=7.0 mmol/L or glycated haemoglobin (HbA1c) level >=6.5% (48 mmol/mol) would be identified as overt diabetes Glucose levels associated with an arbitrary 1.75-fold increase risk above the mean (from HAPO results) for birth weight, cord C peptide concentration, and percentage body fat being above the 90th centile would constitute a diagnosis of gestational diabetes Only one abnormal value would be needed for diagnosis since fasting, one hour, and two hour glucose values were all associated with the defined adverse outcomes Two step testing could be abandoned in favour of a single oral glucose tolerance test. ...all of these unwelcome outcomes have other risk factors, most notably maternal obesity and gestational weight gain. 19 20 21 Separating out the role of gestational diabetes is difficult-the randomised controlled trials that showed benefit from treating gestational diabetes also ameliorated weight gain in the mothers; 13 14 the risks of obesity and glucose intolerance in the offspring associated with gestational diabetes are lost when maternal body mass index is factored into the analysis. 22 Overall, 78% of large for gestational age babies in HAPO were born to women with normal glucose tolerance. 23 We need to understand better how these factors interact to increase risks and to manage them, and not assume that lowering minimally raised blood sugar values is of paramount importance.
...the intervention group babies were slightly heavier at 3,742 vs. 3,593 g. Recent meta-analyses showed similar patterns: weight gain in pregnancy can be attenuated by intervention, but birth weight ...is unchanged (10-12). (17) showed similar results, with maternal weight and weight gain but not glucose being predictors of LGA, and these metabolic factors only accounted for 26% of LGA. ...in study populations that include women diagnosed as GDM by the new ADA criteria obesity appears to play a more important role in determining LGA but, all told, three-quarters of LGA remains unexplained by maternal obesity, weight gain, or glucose.
Patients with Type I Diabetes (T1D) must take insulin injections to prevent the serious long term effects of hyperglycemia. They must also be careful not to inject too much insulin because this could ...induce (potentially fatal) hypoglycemia. Patients therefore follow a “regimen” that determines how much insulin to inject at each time, based on various measurements. We can produce an effective regimen if we can accurately predict a patient’s future blood glucose (BG) values from his/her current features. This study explores the challenges of predicting future BG by applying a number of machine learning algorithms, as well as various data preprocessing variations (corresponding to 312 learner, preprocessed-dataset combinations), to a new T1D dataset that contains 29,601 entries from 47 different patients. Our most accurate predictor, a weighted ensemble of two Gaussian Process Regression models, achieved a (cross-validation)
e
r
r
L
1
loss of 2.7 mmol/L (48.65 mg/dl). This result was unexpectedly poor given that one can obtain an
e
r
r
L
1
of 2.9 mmol/L (52.43 mg/dl) using the naive approach of simply predicting the patient’s average BG. These results suggest that the diabetes diary data that is typically collected may be insufficient to produce accurate BG prediction models; additional data may be necessary to build accurate BG prediction models over hours.
Aim: To examine the association between elevated maternal fasting plasma glucose (FPG) during pregnancy and obesity in the offspring.
Methods: For women without pre-existing diabetes in 2 zones in ...Alberta, Canada with births between 2005 - 2013, maternal data were linked to offspring’s birth registry and preschool immunization records (w/height, weight) between 2009-2017. A 50-g glucose challenge test (GCT) followed by a 75-g OGTT was used to diagnose GDM. Pregnancies were grouped as follows: 1) GCT negative; 2) OGTT negative; 3) elevated FPG on the OGTT; and 4) elevated 1-hour and/or 2-hour OGTT only. WHO criteria were used to identify children who were overweight, obese, or extremely obese.
Results: Of 79,156 pregnancies, 80.3% were GCT negative, 14.7% were OGTT negative, 1.3% had elevated FPG, and 3.7% had elevated post-load glucose only. Both LGA and pre-school obesity rates were highest in pregnancies with abnormal FPG (Figure). Relative to children of GCT negative pregnancies, children of pregnancies with elevated maternal FPG had adjusted odds ratio (aOR, 95% CI) 3.0, (2.6-3.6) for LGA; and aOR 1.3 (1.1 - 1.6) for overweight, aOR 2.4 (1.9 - 3.0) for obesity, aOR 3.5 (2.7 - 4.7) for extreme obesity at preschool age.
Conclusion: The effect of elevated maternal FPG in pregnancy on offspring weight extends to early childhood. These children may be candidates for early pediatric weight and health interventions.
Disclosure
P. Kaul: None. A. Savu: None. L.E. Moore: None. R.O. Yeung: Research Support; Self; AstraZeneca, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck & Co., Inc. E.A. Ryan: None.
Funding
Canadian Institutes of Health Research; University Hospital Foundation
When we hear of an 11-pound baby being delivered, maternal diabetes comes to mind. This link between the mother's glucose levels and macrosomia provides the main rationale for treating gestational ...diabetes. Recently proposed criteria for gestational diabetes will result in the condition being diagnosed in nearly a fifth of all pregnancies.1 In a related article in CMAJ, Retnakaran and colleagues report that, among women who did not have gestational diabetes according to current diagnostic criteria, im paired glucose tolerance was not a significant independent pre dictor of having a large-for- gestational-age infant.2 Given that many of these women would be la belled as having gestational diabetes using the proposed diagnostic criteria,1 this should give us pause before accepting such changes to the criteria. Many studies have shown an association be - tween macrosomia and maternal diabetes. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study (n = 23 316) showed a continuous association between increased infant birth weight and maternal glucose levels below those diagnostic of diabetes.3 In 1952, Pedersen hypothesized that excess maternal glucose crosses the placenta and leads to fetal hyperglycemia, which in turn leads to hyperinsulinemia and excessive fetal growth.4 In large-for-gestational-age infants of women with diabetes, the excess weight is not simply from the glucose being turned into fat, but many internal organs are enlarged as well. Currently, the best explanation may be that an elevated fetal insulin level downregulates insulin growth factor (IGF)- binding protein-1, which allows more unbound IGF-1 to promote excess growth. The large HAPO study showed that the association between maternal glucose levels and birth weight is a continuum with no clear threshold.3 The International Association of Diabetes and Pregnancy Study Groups came to a consensus in choosing diagnostic thresholds of 5.1, 10.0 and 8.5 mmol/L for fasting, one-hour and two-hour plasma glucose concentrations, respectively, on a single 75-g oral glucose tolerance test.1 These thresholds are based on the glucose levels associated with a 1.75-fold increased risk of having a large-forgestational- age infant based on data from the HAPO study. The Canadian Diabetes Association's current guidelines for diagnosing gestational diabetes use higher thresholds for glucose levels that are virtually identical to those associated with a 2-fold increased risk of a large-for-gestationalage infant based on the HAPO data.6
PDF
