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Aims/hypothesis Several genome-wide linkage studies have shown an association between diabetic nephropathy and a locus on chromosome 18q harbouring two carnosinase genes, CNDP1 and CNDP2 . Carnosinase degrades carnosine (β-alanyl- l- histidine), which has been ascribed a renal protective effect as a scavenger of reactive oxygen species. We investigated the putative associations of genetic variants in CNDP1 and CNDP2 with diabetic nephropathy (defined either as micro- or macroalbuminuria) and estimated GFR in type 2 diabetic patients from Sweden. Methods We genotyped nine single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (D18S880, five to seven leucine repeats) in CNDP1 and CNDP2 in a case–control set-up including 4,888 unrelated type 2 diabetic patients (with and without nephropathy) from Sweden (Scania Diabetes Registry). Results Two SNPs, rs2346061 in CNDP1 and rs7577 in CNDP2 , were associated with an increased risk of diabetic nephropathy (rs2346061 p  = 5.07 × 10 −4 ; rs7577 p  = 0.021). The latter was also associated with estimated GFR ( β  = −0.037, p  = 0.014), particularly in women. A haplotype including these SNPs (C-C-G) was associated with a threefold increased risk of diabetic nephropathy (OR 2.98, 95% CI 2.43–3.67, p  < 0.0001). Conclusions/interpretation These data suggest that common variants in CNDP1 and CNDP2 play a role in susceptibility to kidney disease in patients with type 2 diabetes.

Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. D Tripathy , M Carlsson , P Almgren , B Isomaa , M R Taskinen , T Tuomi and L C Groop Department of Endocrinology, Malmö University Hospital, Lund University, Sweden. dtripathy@hotmail.com Abstract Recently, a new stage in glucose tolerance, impaired fasting glucose (IFG) (fasting plasma glucose level of 6.1-6.9 mmol/l), was introduced in addition to impaired glucose tolerance (IGT) (2-h glucose level of 7.8-11.0 mmol/l). It is not clear whether IFG and IGT differ with respect to insulin secretion or sensitivity. To address this question, we estimated insulin secretion (by measuring both insulin levels and the ratio of insulin-to-glucose levels in 30-min intervals) and insulin sensitivity (by using the homeostasis model assessment [HOMA] index) from an oral glucose tolerance test (OGTT) in 5,396 individuals from the Botnia Study who had varying degrees of glucose tolerance. There was poor concordance between IFG and IGT: only 36% (303 of 840) of the subjects with IFG had IGT, whereas 62% (493 of 796) of the subjects with IGT did not have IFG. Compared with subjects with normal glucose tolerance (NGT), subjects with IFG were more insulin resistant (HOMA-insulin resistance [IR] values 2.64 +/- 0.08 vs. 1.73 +/- 0.03, P < 0.0005), had greater insulin responses during an OGTT (P = 0.0001), had higher waist-to-hip ratios (P < 0.005), had higher triglyceride and total cholesterol concentrations (P < 0.0005), and had lower HDL cholesterol concentrations (P = 0.0001). Compared with subjects with IFG, subjects with IGT had a lower incremental 30-min insulin-to-glucose area during an OGTT (13.8 +/- 1.7 vs. 21.7 +/- 1.7, P = 0.0008). Compared with subjects with IGT, subjects with mild diabetes (fasting plasma glucose levels <7.8 mmol/l) showed markedly impaired insulin secretion that could no longer compensate for IR and elevated glucose levels. A progressive decline in insulin sensitivity was observed when moving from NGT to IGT and to subjects with diabetes (P < 0.05 for trend), whereas insulin secretion followed an inverted U-shaped form. We conclude that IFG is characterized by basal IR and other features of the metabolic syndrome, whereas subjects with IGT have impaired insulin secretion in relation to glucose concentrations. An absolute decompensation of beta-cell function characterizes the transition from IGT to mild diabetes.

Aims/hypothesis We studied the impact of a family history of type 2 diabetes on physical fitness, lifestyle factors and diabetes-related metabolic factors. Methods The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study is a population-based study in Western Finland, which includes a random sample of 5,208 individuals aged 18 to 75 years identified through the national Finnish Population Registry. Physical activity, dietary habits and family history of type 2 diabetes were assessed by questionnaires and physical fitness by a validated 2 km walking test. Insulin secretion and action were assessed based upon OGTT measurements of insulin and glucose. Results A family history of type 2 diabetes was associated with a 2.4-fold risk of diabetes and lower physical fitness (maximal aerobic capacity 29.2 ± 7.2 vs 32.1 ± 7.0, p = 0.01) despite having similar reported physical activity to that of individuals with no family history. The same individuals also had reduced insulin secretion adjusted for insulin resistance, i.e. disposition index (p < 0.001) despite having higher BMI (27.4 ± 4.6 vs 26.0 ± 4.3 kg/m², p < 0.001). Conclusions/interpretation Individuals with a family history of type 2 diabetes are characterised by lower physical fitness, which cannot solely be explained by lower physical activity. They also have an impaired capacity of beta cells to compensate for an increase in insulin resistance imposed by an increase in BMI. These defects should be important targets for interventions aiming at preventing type 2 diabetes in individuals with inherited susceptibility to the disease.

Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. T Tuomi , A Carlsson , H Li , B Isomaa , A Miettinen , A Nilsson , M Nissén , B O Ehrnström , B Forsén , B Snickars , K Lahti , C Forsblom , C Saloranta , M R Taskinen and L C Groop Department of Endocrinology, Lund University, Sweden. tiinamaija.tuomi@endo.mas.lu.se Abstract The aim of the study was 1) to establish the prevalence of GAD antibodies (GADab) in a population-based study of type 2 diabetes in western Finland, 2) to genetically and phenotypically characterize this subgroup, and 3) to provide a definition for latent autoimmune diabetes in adults (LADA). The prevalence of GADab was 9.3% among 1,122 type 2 diabetic patients, 3.6% among 558 impaired glucose tolerance (IGT) subjects, and 4.4% among 383 nondiabetic control subjects. Islet antigen 2 antibodies (IA2ab) or islet cell antibodies were detected in only 0.5% of the GADab- patients. The GADab+ patients had lower fasting C-peptide concentrations (median [interquartile range]: 0.46 [0.45] vs. 0.62 [0.44] nmol/l, P = 0.0002) and lower insulin response to oral glucose compared with GADab- patients. With respect to features of the metabolic syndrome, the GADab+ patients had lower systolic (140 [29.1] vs. 148 [26.0] mmHg, P = 0.009) and diastolic (79.2 [17.6] vs. 81.0 [13.1] mmHg, P = 0.030) blood pressure values, as well as lower triglyceride concentrations (1.40 [1.18] vs. 1.75 [1.25] mmol/l, P = 0.003). GADab+ men had a lower waist-to-hip ratio compared with GADab- patients. Compared with GADab- patients and control subjects, the GADab+ patients had an increased frequency HLA-DQB1*0201/0302 (13 vs. 4%; P = 0.002) and other genotypes containing the *0302 allele (22 vs. 12%; P = 0.010). However, the frequency of these high-risk genotypes was significantly lower in GADab+ type 2 patients than in type 1 diabetes of young or adult onset (0201/0302 or 0302/X: 36 vs. 66 vs. 64%, P < 0.001). The GADab+ type 2 group did not differ from control subjects with respect to genotypes containing the protective DQB1-alleles *0602 or *0603, nor with respect to the type 1 high-risk genotype in the IDDM1 (Hph1 +/+). We conclude that GADab+ patients differ from both GADab- type 2 diabetic patients and type 1 diabetic patients with respect to beta-cell function, features of the metabolic syndrome, and type 1 diabetes susceptibility genes. Further, we propose that LADA be defined as GADab positivity (>5 relative units) in patients older than 35 years at onset of type 2 diabetes.

Aims/hypothesis Early environmental factors and genetic variants have been reported to be involved in the pathogenesis of type 2 diabetes. The aim of this study was to investigate whether there is an interaction between birthweight and common variants in the TCF7L2 , HHEX , PPARG , KCNJ11 , SLC30A8 , IGF2BP2 , CDKAL1 , CDKN2A/2B and JAZF1 genes in the risk of developing type 2 diabetes. Methods A total of 2,003 participants from the Helsinki Birth Cohort Study, 311 of whom were diagnosed with type 2 diabetes by an OGTT, were genotyped for the specified variants. Indices for insulin sensitivity and secretion were calculated. Results Low birthweight was associated with type 2 diabetes ( p  = 0.008) and impaired insulin secretion ( p  = 0.04). Of the tested variants, the risk variant in HHEX showed a trend towards a low birthweight ( p  = 0.09) and the risk variant in the CDKN2A/2B locus was associated with high birthweight ( p  = 0.01). The TCF7L2 risk allele was associated with increased risk of type 2 diabetes. Pooling across all nine genes, each risk allele increased the risk of type 2 diabetes by 11%. Risk variants in the HHEX , CDKN2A/2B and JAZF1 genes interacted with birthweight, so that the risk of type 2 diabetes was highest in those with lower birthweight ( p  ≤ 0.05). The interaction was also present in the pooled data. Conclusions/interpretation Low birthweight might affect the strength of the association of some common variants ( HHEX , CDKN2A/2B and JAZF1 ) with type 2 diabetes. These findings need to be replicated in independent cohorts.

Objective: To study the possibility of improving blood lipids, glucose tolerance and insulin sensitivity in women with impaired glucose tolerance and a history of gestational diabetes by merely changing the glycaemic index (GI) and dietary fibre (DF) content of their bread. Design: Randomized crossover study where test subjects were given either low GI/high DF or high GI/low DF bread products during two consecutive 3-week periods, separated by a 3-week washout period. An intravenous glucose tolerance test followed by a euglycaemic-hyperinsulinaemic clamp was performed on days 1 and 21 in both the high- and low-GI periods, to assess insulin secretion and insulin sensitivity. Blood samples were also collected on days 1 and 21 for analysis of fasting levels of glucose, insulin, HDL-cholesterol and triacylglycerols (TG). Setting: Lund University, Sweden. Subjects: Seven women with impaired glucose tolerance. Results: The study shows that a modest dietary modification, confined to a lowering of the GI character and increasing cereal DF of the bread products, improved insulin economy as judged from the fact that all women lowered their insulin responses to the intravenous glucose challenge on average by 35% (0-60 min), in the absence of effect on glycaemia. No changes were found in fasting levels of glucose, insulin, HDL-cholesterol or TG. Conclusion: It is concluded that a combination of low GI and a high content of cereal DF has a beneficial effect on insulin economy in women at risk of developing type II diabetes. This is in accordance with epidemiological data, suggesting that a low dietary GI and/or increased intake of whole grain prevent against development of type II diabetes. Sponsorship: Supported by grants from Cerealia Research Foundation.

Aims/hypothesis Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients. Methods In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide. Results Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p = 9.4x10⁻³⁴; 45% vs 18%, p = 1.4 x 10⁻¹⁶), PTPN22 CT/TT (34% vs 26%, p = 0.0023; 31% vs 23%, p = 0.034), INS VNTR class I/I (69% vs 53%, p = 1.3 x 10⁻⁸; 69% vs 51%, p = 8.5 x 10⁻⁵) and INS VNTR class IIIA/IIIA (75% vs 63%, p = 4.3 x 10⁻⁶; 73% vs 60%, p = 0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p = 0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%). Conclusions/interpretation Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.

Aims/hypothesis Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association. Methods A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created. Results A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history. Conclusions/interpretation Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.

We studied whether there is an association between the single nucleotide polymorphism c.533A>C (K121Q) in the glycoprotein PC-1 gene and features of the metabolic syndrome in case-control and intrafamily association studies in 922 subjects from Finland and Sweden. No difference was observed in the Q allele frequency between control subjects and type 2 diabetic subjects (12.9 vs. 15.1%). The QK genotype was associated with higher fasting plasma glucose (FPG) concentrations than the KK genotype in type 2 diabetic patients (P <0.001) and their relatives (P <0.05). A permutation test of siblings discordant for the QK and KK genotypes also showed that the nondiabetic siblings with the QK genotype had higher FPG (6.1 +/- 2.0 vs. 5.4 +/- 0.6 mmo/l, P <0.001) and fasting insulin (7.0 +/- 3.6 vs. 4.8 +/- 2.6 mU/l, P <0.05) concentrations than the carriers of the KK genotype. In addition, diabetic siblings with the QK genotype had higher systolic blood pressure (147.0 +/- 18.0 vs. 140.0 +/- 18.7 mmHg, P <0.05) and higher fasting (9.9 +/- 3.0 vs. 8.8 +/- 2.8 mmol/l, P <0.05) and 2-h plasma glucose (17.3 +/- 8.5 vs. 12.9 +/- 4.2 mmol/l, P < 0.05) concentrations than the diabetic carriers of the KK genotype. The present study shows that, although the Q allele of the human glycoprotein PC-1 gene is associated with surrogate measures of insulin resistance, it may not be enough to increase the susceptibility to type 2 diabetes.

To study whether albumin excretion rate is an inherited trait in families of patients with Type II (non-insulin-dependent) diabetes mellitus. We used three different approaches. Heritability of albumin excretion rate was studied in 267 nuclear families from the Botnia Study in Western Finland using parent-offspring regression. Albumin excretion rate was also measured in 206 non-diabetic offspring of 119 Type II diabetic parents with or without albuminuria (albumin excretion rate > 20 microg/min). Finally, albumin excretion rate was measured in altogether 652 siblings of 74 microalbuminuric and 320 normoalbuminuric probands. To study the potential confounding effect of blood pressure, the heritability of blood pressure was estimated in 718 nuclear families. Using parent-offspring regression, the heritability of albumin excretion rate was about 30 %, being the strongest from mothers to sons (35-39 % resemblance). The heritability for systolic blood pressure ranged from 10 to 20 % and for diastolic blood pressure from 10 to 27 %. Offspring of albuminuric Type II diabetic parents had higher albumin excretion rates (median 5.4 [range 1.0-195] vs 4.0 [1.0-23] microg/min, p = 0. 0001) and a higher frequency of microalbuminuria (11 vs 2 %, p = 0. 012) than offspring of normoalbuminuric parents. Further, siblings of microalbuminuric probands had higher albumin excretion rates than siblings of normoalbuminuric probands (4.1 [0.6-14.5] vs 3.6 [0.2-14. 4] microg/min, p < 0.01). The data suggest that albumin excretion rate is an inherited trait in families of patients with Type II diabetes. [Diabetologia (1999) 42: 1359-1366]