Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to ...individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.
We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA
, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.
We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.
We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.
Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhälsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research.
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or ...genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Celotno besedilo
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The association between low birth weight and raised blood pressure has been extensively replicated. Little is known about the way childhood growth modifies the effects of low birth weight. We report ...on the fetal and childhood growth of 1958 men and women who received treatment for hypertension and belong to a cohort of 7086 people born in Helsinki, Finland, during 1924–1933. As expected, the men and women who developed hypertension had low birth weight (P =0.002). They were also shorter in body length at birth (P =0.02). After birth they experienced accelerated growth, so that by 7 years their heights and weights were approximately average. In a simultaneous regression, both birth length and tall height had statistically significant although opposing effects on hypertension (P =0.003 for birth length and 0.009 for height at 7 years). Accelerated postnatal growth was associated with better childhood living conditions. Children who later developed both hypertension and type 2 diabetes, rather than hypertension alone, had small placental size as well as small body size at birth, and their accelerated postnatal growth continued beyond 7 years. We suggest that hypertension may originate through retarded growth in utero followed by accelerated postnatal growth as a result of good living conditions. Retarded fetal growth leads to permanently reduced cell numbers in the kidney and other tissues, and subsequent accelerated growth may lead to excessive metabolic demand on this limited cell mass.
Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined.
To conduct a ...quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults.
Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included.
Estimates of association (odds ratio OR per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations.
Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66%; 95% confidence interval CI, 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 95% CI, 0.70-0.82 before adjustment and 0.70 95% CI, 0.65-0.76 after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 95% CI, 0.70-0.84 before adjustment and 0.78 95% CI, 0.72-0.84 after adjustment). There was no strong evidence of publication or small study bias.
In most populations studied, birth weight was inversely related to type 2 diabetes risk.
Pathways of Infant and Childhood Growth That Lead to Type 2 Diabetes
Johan G. Eriksson , MD, PHD 1 ,
Tom J. Forsen , MD, PHD 1 2 ,
Clive Osmond , PHD 3 and
David J.P. Barker , FRC 3
1 National Public ...Health Institute, Department of Epidemiology and Health Promotion, Diabetes and Genetic Epidemiology Unit,
Helsinki, Finland
2 University of Helsinki, Department of Public Health, Helsinki, Finland
3 MRC Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, U.K
Address correspondence and reprint requests to Dr. Johan Eriksson, National Public Health Institute, Department of Epidemiology
and Health Promotion, Diabetes and Genetic Epidemiology Unit, Mannerheimintie 166, FIN-00300, Helsinki, Finland. E-mail: johan.eriksson{at}ktl.fi
Abstract
OBJECTIVE —Although a link between small body size at birth and later type 2 diabetes has been repeatedly documented, less is known
about the associations between the disease and growth during infancy. The aim of this study was to explore the pathways of
infant and early growth that lead to type 2 diabetes in adult life.
RESEARCH DESIGN AND METHODS —We carried out a longitudinal study of 8,760 subjects born in Helsinki from 1934 to 1944. On average, they had 8 measurements
of height and weight between birth and 1 year of age and another 10 measurements between 1 and 12 years of age. We identified
people with type 2 diabetes using a national register.
RESULTS —Among babies whose birth weights were ≤3.5 kg, the rate of infant growth was unrelated to later type 2 diabetes. Among babies
with birth weights >3.5 kg, slow growth in length between birth and 3 months of age predicted later disease. Rapid gain in
BMI after age 2 years increased the risk of later disease in both groups of babies, but this effect was greatest among children
who had slow growth in length between birth and 3 months of age. In children whose Z-scores for length decreased, an SD increase
in BMI at age 12 years was associated with an odds ratio (OR) for type 2 diabetes of 1.77 (95% CI 1.50–2.09). The corresponding
OR in subjects whose Z-scores for length increased was 1.42 (95% CI 1.20–1.69). Rapid gain in childhood BMI was associated
with high maternal BMI and socioeconomic factors (fewer people in the home and lower social class).
CONCLUSIONS —Babies with above-average birth weights may develop type 2 diabetes later in life if poor living conditions lead to faltering
growth in length in the first few months after birth. We speculate that growth faltering at this time is associated with lifelong
impairment of insulin metabolism and inability to meet the challenge of rapid childhood increase in BMI.
Footnotes
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Accepted August 4, 2003.
Received March 10, 2003.
DIABETES CARE
Highlights • Hypoglycemia has a major impact on patients’ daily lives and diabetes management. • There are large regional variations in patients’ response to hypoglycaemia. • Patient education ...programmes need to place greater emphasis on the avoidance and management of hypoglycemic events.
Maternal and Social Origins of Hypertension Barker, David J.P; Osmond, Clive; Forsen, Tom J ...
Hypertension (Dallas, Tex. 1979),
2007-September, 2007-Sep, 2007-09-00, 20070901, Letnik:
50, Številka:
3
Journal Article
Recenzirano
Odprti dostop
We previously reported that in 2003 people from the Helsinki birth cohort whose blood pressures were measured, 2 different paths of growth preceded the development of hypertension. People already ...diagnosed with hypertension were small at birth but of average body size at age 11 years. People newly diagnosed with hypertension grew slowly in utero and through childhood. We have now examined how the motherʼs body size, placental size, and living conditions after birth, 3 influences that affect growth, affect hypertension. Diagnosed hypertension was associated with low placental weight and poor living conditions after birth. The odds ratios were 1.6 (95% CI, 1.1 to 2.3) in people with placental weights <550 g, compared with those with weights >750 g, and 2.2 (95% CI, 1.5 to 3.3) in people whose fathers were laborers compared with those in upper middle-class families. Newly diagnosed hypertension was associated with a small anteroposterior diameter of the motherʼs bony pelvis, a known consequence of rickets or lesser degrees of malnutrition in infancy. The odds ratio was 2.2 (95% CI, 1.4 to 3.5) in people whose mothersʼ pelvic external conjugate diameters were <18 cm when compared with people whose mothersʼ diameters were ≥19 cm. We conclude that one path of growth that leads to hypertension is initiated by fetal undernutrition, which may make a baby vulnerable to postnatal stress, whereas the other originates in a functional incapacity in the motherʼs metabolism, possibly protein metabolism, which she acquired through undernutrition during her infancy.
Low birth weight and high childhood body mass index (BMI) is each associated with an increased risk of coronary heart disease (CHD) in adult life. We studied individual and combined associations of ...birth weight and childhood BMI with the risk of CHD in adulthood.
Birth weight and BMI at age seven years were available in 216,771 Danish and Finnish individuals born 1924-1976. Linkage to national registers for hospitalization and causes of death identified 8,805 CHD events during up to 33 years of follow-up (median = 24 years) after age 25 years. Analyses were conducted with Cox regression based on restricted cubic splines. Using median birth weight of 3.4 kg as reference, a non-linear relation between birth weight and CHD was found. It was not significantly different between cohorts, or between men and women, nor was the association altered by childhood BMI. For birth weights below 3.4 kg, the risk of CHD increased linearly and reached 1.28 (95% confidence limits: 1.13 to 1.44) at 2 kg. Above 3.4 kg the association weakened, and from about 4 kg there was virtually no association. BMI at age seven years was strongly positively associated with the risk of CHD and the relation was not altered by birth weight. The excess risk in individuals with a birth weight of 2.5 kg and a BMI of 17.7 kg/m(2) at age seven years was 44% (95% CI: 30% to 59%) compared with individuals with median values of birth weight (3.4 kg) and BMI (15.3 kg/m(2)).
Birth weight and BMI at age seven years appeared independently associated with the risk of CHD in adulthood. From a public health perspective we suggest that particular attention should be paid to children with a birth weight below the average in combination with excess relative weight in childhood.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims/hypothesis
Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition ...with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA).
Methods
We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (
n
= 911) or type 1 diabetes (
n
= 406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (
n
= 4,002).
Results
Variants in the
ZMIZ1
(rs12571751,
p
= 4.1 × 10
−5
) and
TCF7L2
(rs7903146,
p
= 5.8 × 10
−4
) loci were strongly associated with LADA. Variants in the
KCNQ1
(rs2237895,
p
= 0.0012),
HHEX
(rs1111875,
p
= 0.0024 in Finns) and
MTNR1B
(rs10830963,
p
= 0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the
KLHDC5
(rs10842994,
p
= 9.5 × 10
−4
in Finns),
TP53INP1
(rs896854,
p
= 0.005),
CDKAL1
(rs7756992,
p
= 7.0 × 10
−4
; rs7754840,
p
= 8.8 × 10
−4
) and
PROX1
(rs340874,
p
= 0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for
MTNR1B
(rs10830963,
p
= 3.2 × 10
−6
) and
HNF1A
(rs2650000,
p
= 0.0012).
Conclusions/interpretation
LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.
Objective: We assessed the prevalence and consequences of discordant language communication between bilingual Swedish speaking emergency patients and general practitioners (GPs) in Finnish ...healthcare. We compared the results with Finnish speaking emergency patients provided with language concordant healthcare. Materials and Methods: A researcher-designed questionnaire was used to collect data about both Swedish and Finnish speaking emergency patients' health and socioeconomic status, reason for emergency visits and use of healthcare. Furthermore, the Swedish speakers' nonnative language proficiency and preferred communication language were examined. The study was performed in 16 healthcare centers and outpatient departments in bilingual regions in Finland. Results: The Swedish speakers (n = 139) visited healthcare centers less than the Finnish speakers (n = 736) (P = 0.001) and communicated less frequently with the GP in their native language (P < 0.001). The Swedish speakers more often planned to revisit their assigned GP (P < 0.001) after the emergency visit. No differences in health conditions and socioeconomic status between the language groups were observed. Conclusion: Although Swedish and Finnish speaking emergency patients report a similar prevalence of chronic noncommunicable diseases, Swedish speakers make fewer annual visits to a physician. We suggest that discordant language communication might relate to decreased healthcare visits among bilingual Swedish speaking emergency patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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