Helena Elding Larsson

Diabetes-associated HLA genotypes affect birthweight in the general population.

Aims/hypothesisThe aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight.MethodsHLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW).ResultsGenotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08–1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56–0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors.Conclusions/interpretationHLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.

Glucose-dependent arginine stimulation test for characterization of islet function: studies on reproducibility and priming effect of arginine.

Summary Quantitative determination of insulin secretion is of importance both clinically and in research. The optimal method has not been established, although several different methods have been used. We determined the reproducibility of islet function parameters obtained by the glucose-dependent arginine stimulation test, and also studied the priming effect of arginine on subsequent acute insulin responses. The test measures the acute insulin (AIR) and glucagon (AGR) responses to i. v. arginine (5 g injected over 45 s) at fasting glucose and glucose concentrations clamped at 14 and above 25 mmol/l, as well as the glucose potentiation of insulin secretion (slopeAIR) and the glucose inhibition of glucagon secretion (slopeAGR). When the test was performed twice in seven healthy women (mean ± SD age 58.7 ± 0.5 years, BMI 27.6 ± 5.5 kg/m2), the AIRs to arginine had a within-subject coefficient of variation (CV) of 18.6 % at fasting glucose, 18.7 % at 14 mmol/l glucose and 16.3 % at above 25 mmol/l glucose. The CVs for AGR were 11.6, 14.9 and 8.9 %, respectively. The CV of the slopeAIR was 24 % and of the slopeAGR 17.2 %. The arginine priming study was performed in six healthy women (age 63.7 ± 0.3 years, BMI 28.0 ± 6.9 kg/m2). Saline or arginine (5 g) was injected at fasting glucose, followed by arginine (5 g) at 14 mmol/l glucose. There was no difference between the acute insulin or glucagon responses to arginine at 14 mmol/l glucose in the two conditions, suggesting that there is no priming effect of arginine on the subsequent acute insulin or glucagon responses. Therefore, this method is a good tool to determine insulin secretion as, apart from its good reproducibility, it also provides several important parameters of islet function. [Diabetologia (1998) 41: 772–777]

Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations

Abstract.Aims/hypothesis: We aimed to examine whether impaired glucose tolerance is associated with reduced suppression of glucagon concentrations. Methods: Eighty-four non-diabetic women of Caucasian origin and 61 years of age, of whom 48 had normal glucose tolerance (NGT) and 36 had IGT, underwent a 75 g OGTT and a hyperinsulinaemic, euglycaemic clamp with measurement of glucagon, insulin and glucose concentrations. Results: At 2 h after 75 g oral glucose, glucagon concentrations were reduced by 7.1 ± 1.1 ng/l in NGT vs 8.0 ± 1.4 ng/l in IGT, (NS). However, the 2 h reductions in glucagon per mmol/l increase in 2 h glucose or per pmol/l increase in 2 h insulin were both impaired in IGT (p = 0.002 and p = 0.043, respectively) because the 2 h increases in glucose and insulin were higher in IGT than in NGT. Furthermore, suppression of glucagon concentrations during a euglycaemic clamp at hyperinsulinaemic concentrations (NGT: 607 ± 19 pmol/l, IGT: 561 ± 21 pmol/l) was lower in IGT (13.6 ± 1.6 ng/l) than in NGT (23.1 ± 1.2 ng/l; p < 0.001). The suppression of glucagon concentrations during the hyperinsulinaemic, euglycaemic clamp correlated with insulin sensitivity (r = 0.24, p = 0.027) and with the 2 h glucose value during the OGTT (r = –0.52, p < 0.001). Conclusion/interpretation: Impaired glucose tolerance is associated with reduced insulin-induced suppression of glucagon secretion, which could be caused by A-cell insulin resistance. Inappropriately high glucagon secretion could therefore contribute to the metabolic perturbations in IGT. [Diabetologia (2001) 44: 1998–2003]

Reduced Prevalence of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Young Children Participating in Longitudinal Follow-Up

OBJECTIVE Young children have an unacceptably high prevalence of diabetic ketoacidosis (DKA) at the clinical diagnosis of type 1 diabetes. The aim of this study was to determine whether knowledge of genetic risk and close follow-up for development of islet autoantibodies through participation in The Environmental Determinants of Diabetes in the Young (TEDDY) study results in lower prevalence of DKA at diabetes onset in children aged <2 and <5 years compared with population-based incidence studies and registries. RESEARCH DESIGN AND METHODS Symptoms and laboratory data collected on TEDDY participants diagnosed with type 1 diabetes between 2004 and 2010 were compared with data collected during the similar periods from studies and registries in all TEDDY-participating countries (U.S., SEARCH for Diabetes in Youth Study; Sweden, Swediabkids; Finland, Finnish Pediatric Diabetes Register; and Germany, Diabetes Patienten Verlaufsdokumenation [DPV] Register). RESULTS A total of 40 children younger than age 2 years and 79 children younger than age 5 years were diagnosed with type 1 diabetes in TEDDY as of December 2010. In children <2 years of age at onset, DKA prevalence in TEDDY participants was significantly lower than in all comparative registries (German DPV Register, P < 0.0001; Swediabkids, P = 0.02; SEARCH, P < 0.0001; Finnish Register, P < 0.0001). The prevalence of DKA in TEDDY children diagnosed at <5 years of age (13.1%) was significantly lower compared with SEARCH (36.4%) (P < 0.0001) and the German DPV Register (32.2%) (P < 0.0001) but not compared with Swediabkids or the Finnish Register. CONCLUSIONS Participation in the TEDDY study is associated with reduced risk of DKA at diagnosis of type 1 diabetes in young children.

Immune therapy in type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder directed against the β cells of the pancreatic islets. The genetic risk of the disease is linked to HLA-DQ risk alleles and unknown environmental triggers. In most countries, only 10–15% of children or young adults newly diagnosed with T1DM have a first-degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or the ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may already have developed in children of 1–3 years of age. Immune therapy in T1DM is approached at three different stages. Primary prevention is treatment of individuals at increased genetic risk. For example, one trial is testing if hydrolyzed casein milk formula reduces T1DM incidence in genetically predisposed infants. Secondary prevention is targeted at individuals with persistent islet autoantibodies. Ongoing trials involve nonautoantigen-specific therapies, such as Bacillus Calmette–Guérin vaccine or anti-CD3 monoclonal antibodies, or autoantigen-specific therapies, including oral and nasal insulin or alum-formulated recombinant human GAD65. Trial interventions at onset of T1DM have also included nonautoantigen-specific approaches, and autoantigen-specific therapies, such as proinsulin peptides. Although long-term preservation of β-cell function has been difficult to achieve in many studies, considerable progress is being made through controlled clinical trials and animal investigations towards uncovering mechanisms of β-cell destruction. Novel therapies that prevent islet autoimmunity or halt progressive β-cell destruction are needed.

Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity.

Aims/hypothesis. To establish whether islet compensation to deterioration of insulin action depends on inherent insulin sensitivity. Methods. We examined insulin and glucagon secretion after iv arginine (5 g) at fasting, 14 and greater than 25 mmol/l glucose concentrations before and after lowering of insulin sensitivity by oral dexamethasone (3 mg twice daily for 2 1/2 days) in 10 women with normal glucose tolerance, aged 58 or 59 years. Five women had high insulin sensitivity as shown by euglycaemic, hyperinsulinaemic clamp (99 ± 12 nmol glucose · kg body weight–1· min–1/pmol insulin · l–1; means ± SD) whereas five women had low insulin sensitivity (34 ± 15 nmol glucose · kg body weight–1· min–1/pmol insulin · l–1). Results. Dexamethasone reduced insulin sensitivity in both groups. Fasting insulin concentration increased by dexamethasone in high insulin sensitivity (72 ± 10 vs 49 ± 9 pmol/l, p = 0.043) but not in low insulin sensitivity (148 ± 63 vs 145 ± 78 pmol/l) whereas the fasting glucose concentration increased in low insulin sensitivity (6.5 ± 0.8 vs 5.8 ± 0.6 mmol/l, p = 0.043) but not in high insulin sensitivity (5.3 ± 0.8 vs 5.3 ± 0.6 mmol/l). Fasting glucagon concentration was not changed. Plasma insulin concentrations after raising glucose to 14 and more than 25 mmol/l and the insulin response to arginine at more than 25 mmol/l glucose were increased by dexamethasone in high insulin sensitivity (p < 0.05) but not changed by dexamethasone in low insulin sensitivity. Furthermore, in high but not in low insulin sensitivity, dexamethasone reduced the glucagon response to arginine (p = 0.043). Conclusion/interpretation. The results show that adaptation in islets function to dexamethasone-induced short-term reduction in insulin sensitivity is lacking in subjects with low inherent insulin sensitivity. [Diabetologia (1999) 42: 936–943]

Glucose intolerance is predicted by low insulin secretion and high glucagon secretion : outcome of a prospective study in postmenopausal Caucasian women

Aims/hypothesis. To study the pathophysiological importance of changes in insulin sensitivity and islet function over time for alterations in glucose tolerance in a randomly selected large group of non-diabetic women aged 57–59 years over a 3-year period.¶Methods. At baseline and at the 3-year follow-up, glucose tolerance (WHO 75 g oral glucose), insulin sensitivity (euglycaemic, hyperinsulinaemic clamp) and insulin and glucagon secretion (2 to 5-min responses to 5 g i. v. arginine at fasting, 14 and > 25 mmol/l glucose) were measured.¶Results. At baseline, women with impaired glucose tolerance (IGT, n = 28) had lower insulin sensitivity (p = 0.048) than normal women (NGT, n = 58). The arginine-induced insulin responses (AIR) were inversely associated with insulin sensitivity (r≥– 0.55, p < 0.001). When related to the 3-year follow-up, the baseline product of AIR at 14 mmol/l glucose times insulin sensitivity, insulin effect index (IE) (r = – 0.40, p < 0.001) and the arginine-induced glucagon response at 14 mmol/l glucose (AGR, r = 0.28, p = 0.009) both correlated with follow-up 2-h glucose. In a multiple regression model, baseline 2-h glucose, insulin effect index and arginine-induced glucagon response independently predicted 2-h glucose at follow-up (total r = 0.668, p < 0.001). Furthermore, Δinsulin sensitivity (i. e. follow-up minus baseline) correlated with Δinsulin secretion (r = – 0.30, p = 0.006), whereas Δglucagon secretion correlated with Δ2-h glucose (r = 0.30, p = 0.006) over the 3 years. In a multiple regression, alterations in 2-h glucose over the 3 years were independently determined by changes in fasting insulin and glucagon secretion (r = 0.424, p < 0.001).¶Conclusion/interpretation. Low insulin secretion, when judged in relation to insulin sensitivity, and high glucagon secretion, determine glucose tolerance over time in the individual subject. These processes are therefore potential targets for prevention of deterioration in glucose tolerance. [Diabetologia (2000) 43: 194–202]

Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease.

The Environmental Determinants of Diabetes in the Young (TEDDY) study is designed to identify environmental exposures triggering islet autoimmunity and type 1 diabetes (T1D) in genetically high‐risk children. We describe the first 100 participants diagnosed with T1D, hypothesizing that (i) they are diagnosed at an early stage of disease, (ii) a high proportion are diagnosed by an oral glucose tolerance test (OGTT), and (iii) risk for early T1D is related to country, population, human leukocyte antigen (HLA)‐genotypes and immunological markers.

A comparison of the rheological properties of wheat flour dough and its gluten prepared by ultracentrifugation

Ultracentrifugation has been used as a tool for separating dough into different phases and as dough can be described as a bicontinuous system, gluten forms one phase, and starch another. The aim of this study is to investigate the possibility of using ultracentrifugation to extract gluten from dough. By using this method disadvantages such as excess washing, drying and reconstitution of dried gluten (involving a second mixing) were avoided. Gluten samples were obtained by this method (doughs differing in water content from 42.6 to 47.1%) and the rheological properties of dough and the corresponding gluten were studied in frequency sweep. The gluten coming from dough after ultracentrifugation had water contents in the range of 54.2–58.8%. An increase in water content reduced the storage modulus to a greater extent than the loss modulus for the studied dough. The gluten was not affected to the same extent by an increase in water content, as was the dough. The ratios of G′dough/G′gluten and G″dough/G″gluten approached the value of 1 when the amount of dough water increased. The slope of log G″ versus log for gluten (n″gluten) were always higher than n′gluten. For dough the slope of log G″ versus log (n″dough) were on the same level or higher than (n′dough). It was concluded that both the frequency dependency and the values of G′ and G″ were more or less independent of water content for gluten. On the contrary dough showed a strong dependency of water content in particular for the value of G′ and the frequency dependency of G′. (Less)

Effect of pH and Sodium Chloride on Wheat Flour Dough Properties: Ultracentrifugation and Rheological Measurements

Salt linkages, electrostatic effects, and modified water structure are important for the properties of gluten, wheat flour dough, and baking (Belitz et al 1986). These effects have been studied at various levels of salt concentration, pH, and ion strength (Doguchi and Hlynka 1967; Salovaara 1982; Kinsella and Hale 1984; Holmes and Hoseney 1987 Preston 1989; He et al 1992). Sodium chloride usually shows a strengthening effect on dough properties and a decrease in farinograph absorption (Salovaara 1982; Preston 1989). The opposite effect was found for chaotropic anions at higher salt concentrations, when the effect of neutral salts of the lyotropic series was investigated (Kinsella and Hale 1984; Preston 1989). In baking experiments, these effects are not always observed, probably due to the adjustment of water content to a constant dough mixing resistance (Salovaara 1982). On the other hand, improved baking quality for sodium chloride supplemented doughs has been reported (He et al 1992). Doguchi (1967) reported a linear and moderately increasing relationship between farinograph maximum consistency of Gluten and pH (4.5-6.0). In a later study, the loaf volume of baked bread also increased over the same pH region but decreased at higher pH values (Holmes and Hoseney 1987). Earlier studies showed that the fractions obtained by Ultracentrifugation of dough are sensitive to wheat cultivar, dough water content (Larsson and Eliasson 1996a), mixing time. ascorbic acid, and lipid content (Larsson and Eliasson 1996b). In the present study, the effect on dough properties of sodium chloride at concentrations related to baking and the effect of pH related to those observed in dough prepared with sour dough are reported. Dough properties are characterized by the fractionation of dough in ultracentrifugation and rheological measurements at small oscillating deformation.