| 1. |
- Cretti, A., et al.
(författare)
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Assessment of beta-cell function during the oral glucose tolerance test by a minimal model of insulin secretion
- 2001
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972. ; 31:5, s. 405-416
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Tidskriftsartikel (refereegranskat)abstract
- Objective To characterise the performance of beta -cell during a standard oral glucose tolerance test (OGTT). Design Fifty-six subjects were studied. A minimal analogic model of beta -cell secretion during the OGTT was applied to all OGTTs (see below). The amount of insulin secreted over 120' in response to oral glucose (OGTT-ISR; Insulin Units 120'(-1) m(-2) BSA) and an index of beta -cell secretory 'force' (beta -lndex; pmol.min(-2).m(-2) BSA) were computed with the aid of the model. In protocol A, 10 healthy subjects underwent two repeat 75 g OGTT with frequent (every 10(/)-15(/)) blood sampling for glucose and C-peptide to test the reproducibility of OGTT-ISR and beta -Index with a complete or a reduced data set. In protocol B, 7 healthy subjects underwent three OGTTs (50, 100 or 150 g), to test the stability of the beta -Index under different glucose loads. In protocol C, 29 subjects (15 with normal glucose tolerance, 7 with impaired glucose tolerance and 7 with newly diagnosed type 2 diabetes) underwent two repeat 75 g OGTT with reduced (every 30' for 120') blood sampling to compare the reproducibility and the discriminant ratio (DR) of OGTT-ISR and beta -index with the insulinogenic index (IG-Index: Delta Insulin (30' - Basal)/Delta Glucose (30' - Basal)). In protocol D, 20 subjects (14 with normal glucose tolerance, 5 with impaired glucose tolerance and 1 with newly-diagnosed type 2 diabetes) underwent a 75 g OGTT and an intravenous glucose tolerance test (IVGTT) on separate days to explore the relationships between acute (0'-10') insulin response (ATR) during the IVGTT and beta -index and OGTT-ISR during the OGTT. Results In all protocols, the minimal analogic model of C-peptide secretion achieved a reasonable fit of the experimental data. In protocol A, a good reproducibility of both beta -index and OGTT-ISR was observed with both complete and reduced (every 30') data sets. In protocol B, increasing the oral glucose load caused progressive increases in OGTT-ISR (from 2.63 +/- 0.70 to 5.11 +/- 0.91 Units.120'(-1).m(-2) BSA; P < 0.01), but the -index stayed the same (4.14 +/- 0.35 vs. 4.29 +/- 0.30 vs. 4.30 +/- 0.33 pmol.min(-2).m(-2) BSA). In protocol C, both OGTT-ISR and beta -index had lower day-to-day CVs (17.6 +/- 2.2 and 12.4 +/- 2.4%, respectively) and higher DRs (2.57 and 1.74, respectively) than the IG-index (CV: 35.5 +/- 6.3%; DR: 0.934). OGTT-ISR was positively correlated to BMI (P < 0.03), whereas -index was inversely related to both fasting and 2 h plasma glucose (P < 0.01 for both). In protocol D, -index, but not OGTT-ISR was significantly correlated to ATR (r = 0.542, P < 0.02). Conclusions Analogically modelling -cell function during the OGTT provides a simple, useful tool for the physiological assessment of beta -cell function.
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| 2. |
- Lehtovirta, M, et al.
(författare)
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Metabolic effects of metformin in patients with impaired glucose tolerance
- 2001
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 18:7, s. 578-583
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To assess the effect of metformin on insulin sensitivity, glucose tolerance and components of the metabolic syndrome in patients with impaired glucose tolerance (IGT). METHODS: Forty first-degree relatives of patients with Type 2 diabetes fulfilling WHO criteria for IGT and participating in the Botnia study in Finland were randomized to treatment with either metformin 500 mg b.i.d. or placebo for 6 months. An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp in combination with indirect calorimetry was performed at 0 and 6 months. The patients were followed after stopping treatment for another 6 months in an open trial and a repeat OGTT was performed at 12 months. RESULTS: Metformin treatment resulted in a 20% improvement in insulin-stimulated glucose metabolism (from 28.7 +/- 13 to 34.4 +/- 10.7 micromol/kg fat-free mass (FFM)/min) compared with placebo (P = 0.01), which was primarily due to an increase in glucose oxidation (from 16.6 +/- 3.6 to 19.1 +/- 4.4 micromol/kg FFM; P = 0.03) These changes were associated with a minimal improvement in glucose tolerance, which was maintained after 12 months. CONCLUSIONS: Metformin improves insulin sensitivity in subjects with IGT primarily by reversal of the glucose fatty acid cycle. Obviously large multicentre studies are needed to establish whether these effects are sufficient to prevent progression to manifest Type 2 diabetes and associated cardiovascular morbidity and mortality. Diabet. Med. 18, 578-583 (2001)
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| 3. |
- Martikainen, P., et al.
(författare)
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Brain pathology in three subjects from the same pedigree with presenilin-1 (PSEN1) P264L mutation
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:1, s. 41-54
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Our goal was to assess pathological lesions with respect to type and distribution and to compare these results with the clinical presentation including symptoms and mode of progression in three members of the same pedigree with a P264L presenilin-1 gene mutation. METHODS: We used immunohistochemistry and a tissue microarray technique applied to post mortem brain tissue samples. RESULTS: All three subjects were demented, one subject displayed spastic paraparesis and two had Parkinsonism. All three cases displayed abundant cotton wool plaques composed of amyloid-beta42 but also containing other proteins, for example, hyperphosphorylated tau and in one case TAR DNA binding protein 43. The distribution of the pathology varied and seemed to some extent to be related to the clinical phenotype. An association was detected between neocortical/thalamic involvement and psychiatric symptoms, between striatal/amygdaloid involvement and Parkinsonism, and between brainstem involvement and spastic paraparesis. CONCLUSIONS: Subjects from the same pedigree carrying the same mutation display a clear variability in the type and distribution of pathology as well as in their clinical symptoms. These results emphasize that still unknown factors significantly alter the pathological and clinical phenotypes in genetically predetermined disease.
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| 4. |
- Almgren, Peter, et al.
(författare)
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Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study.
- 2011
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54, s. 2811-2819
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: To study the heritability and familiality of type 2 diabetes and related quantitative traits in families from the Botnia Study in Finland. METHODS: Heritability estimates for type 2 diabetes adjusted for sex, age and BMI are provided for different age groups of type 2 diabetes and for 34 clinical and metabolic traits in 5,810 individuals from 942 families using a variance component model (SOLAR). In addition, family means of these traits and their distribution across families are calculated. RESULTS: The strongest heritability for type 2 diabetes was seen in patients with age at onset 35-60 years (h (2) = 0.69). However, including patients with onset up to 75 years dropped the h (2) estimates to 0.31. Among quantitative traits, the highest h (2) estimates in all individuals and in non-diabetic individuals were seen for lean body mass (h (2) = 0.53-0.65), HDL-cholesterol (0.52-0.61) and suppression of NEFA during OGTT (0.63-0.76) followed by measures of insulin secretion (insulinogenic index [IG(30)] = 0.41-0.50) and insulin action (insulin sensitivity index [ISI] = 0.37-0.40). In contrast, physical activity showed rather low heritability (0.16-0.18), whereas smoking showed strong heritability (0.57-0.59). Family means of these traits differed two- to fivefold between families belonging to the lowest and highest quartile of the trait (p < 0.00001). CONCLUSIONS/INTERPRETATION: To detect stronger genetic effects in type 2 diabetes, it seems reasonable to restrict inclusion of patients to those with age at onset 35-60 years. Sequencing of families with extreme quantitative traits could be an important next step in the dissection of the genetics of type 2 diabetes.
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| 5. |
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| 6. |
- Lehtovirta, M., et al.
(författare)
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Evidence that BMI and type 2 diabetes share only a minor fraction of genetic variance: a follow-up study of 23,585 monozygotic and dizygotic twins from the Finnish Twin Cohort Study
- 2010
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:7, s. 1314-1321
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether BMI predicts type 2 diabetes in twins and to what extent that is explained by common genetic factors. This was a population-based twin cohort study. Monozygotic (n = 4,076) and dizygotic (n = 9,109) non-diabetic twin pairs born before 1958 answered a questionnaire in 1975, from which BMI was obtained. Information on incident cases of diabetes was obtained by linkage to nationwide registers until 2005. Altogether, 1,332 twins (6.3% of men, 5.1% of women) developed type 2 diabetes. The HR for type 2 diabetes increased monotonically with a mean of 1.22 (95% CI 1.20-1.24) per BMI unit and of 1.97 (95% CI 1.87-2.08) per SD of BMI. The HRs for lean, overweight, obese and morbidly obese participants were 0.59, 2.96, 6.80 and 13.64 as compared with normal weight participants. Model heritability estimates for bivariate variance due to an additive genetic component and non-shared environmental component were 75% (men) and 71% (women) for BMI, and 73% and 64%, respectively for type 2 diabetes. The correlations between genetic variance components (r (g)) indicated that one fifth of the covariance of BMI and type 2 diabetes was due to shared genetic influences. Although the mean monozygotic concordance for type 2 diabetes was approximately twice the dizygotic one, age of onset of diabetes within twin pair members varied greatly, irrespective of zygosity. A 28-year follow-up of adult Finnish twins showed that despite high trait heritability estimates, only a fraction of covariation in BMI and incident type 2 diabetes was of genetic origin.
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| 7. |
- Lehtovirta, M, et al.
(författare)
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Heritability of model-derived parameters of beta cell secretion during intravenous and oral glucose tolerance tests: a study of twins
- 2005
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 48:8, s. 1604-1613
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: The genetic architecture of model- derived parameters of beta cell function has never been assessed. Therefore, we estimated heritability (h(2)) for model- derived phenotypes of insulin secretion in twins. Methods: Thirty-three monozygotic (MZ) and 23 dizygotic (DZ) twin pairs from the Finnish Twin Cohort Study underwent OGTT (plasma glucose/C-peptide at 0, 30, 60, 90 and 120 min). A subset of the twin pairs (21 MZ/ 20 DZ) also underwent an IVGTT ( frequent sampling of plasma glucose/ insulin from 0 to 60 min) followed by a 160-min euglycaemic-hyperinsulinaemic clamp (45 mU . min(-1) . m(-2)). Mathematical modelling was applied to the IVGTT and the OGTT to assess first-phase ( readily releasable insulin [RRI]) and second- phase ( sigma) secretion ( IVGTT), and a global index of beta cell performance ( OGTT beta index). Intraclass correlation coefficients and genetic and non-genetic components for trait variances were computed to assess the h(2) of model- derived parameters. Results: The intraclass correlation coefficients in MZ twins were 0.78 for RRI, 0.67 for sigma and 0.57 for OGTT beta index. In DZ twins the correlation coefficients were 0.23, 0.32 and 0.42, respectively. Using the most parsimonious model for each trait, the h(2) - the proportion of variance accounted for by genetic factors - was 76% ( 95% CI: 53 - 88%) for RRI, 28% ( 34 - 80%) for sigma and 53% ( 26 - 72%) for OGTT beta index. Conclusions/ interpretation: Our findings demonstrate that model- derived parameters of insulin secretion have a substantial genetic component and may be used in the search for genetic determinants of beta cell function in humans.
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| 10. |
- Eriksson, JG, et al.
(författare)
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Long-term beneficial effects of glipizide treatment on glucose tolerance in subjects with impaired glucose tolerance
- 2006
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 259:6, s. 553-560
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Tidskriftsartikel (refereegranskat)abstract
- To assess the efficacy and long-term effects of glipizide treatment on glucose and insulin metabolism in individuals with impaired glucose tolerance (IGT). Thirty-seven first-degree relatives of patients with type 2 diabetes fulfilling WHO criteria for IGT were randomized to treatment with either glipizide 2.5 mg once daily or matching placebo for 6 months. A 75 g, 2-h oral (OGTT) and 60 min intravenous glucose tolerance test (IVGTT) were performed at baseline and after 6 months. The subjects were followed up for another 12 months after discontinuation of treatment and a repeat OGTT was performed at 18 months. Thirty-three subjects fulfilled the study. Markers of insulin sensitivity - i.e. fasting insulin and HOMA(IR)-index - improved in the glipizide group (P = 0.04 and 0.02 respectively) as well as HDL cholesterol (P = 0.05) compared with placebo group after 6 months. At 18 months, both fasting and 2 h glucose concentrations were significantly lower in the glipizide group compared with the placebo group (P = 0.04 and 0.03 respectively). The prevalence of type 2 diabetes was 29.4% in the placebo group and 5.9% in the glipizide group at 18 months. This equals an 80% relative risk reduction in the active treatment group. Short-term treatment with glipizide improves glucose and insulin metabolism in subjects with IGT primarily by improving insulin sensitivity mediated by lowering glucose toxicity, thereby providing the beta cells rest. Larger studies are needed to establish whether these effects are sufficient to prevent progression to manifest type 2 diabetes and associated cardiovascular morbidity in subjects at increased risk of developing type 2 diabetes.
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