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  • 1
    Electronic Resource
    Electronic Resource
    A paired-sibling analysis of the XbaI polymorphism in the muscle glycogen synthase gene (1999)
    Springer
    Diabetologia 42 (1999), S. 1138-1145 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Muscle glycogen synthase gene ; GYS1 ; paired-sibling analysis ; Type II diabetes ; hypertension ; metabolic syndrome ; chromosome 19 ; candidate gene ; myocardial infarction ; microalbuminuria.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. We have previously shown an association between a XbaI polymorphism in the muscle glycogen synthase gene (GYS1) and both Type II (non–insulin–dependent) diabetes mellitus and hypertension. Association studies are, however, hampered by the selection of the control group. To circumvent these problems we addressed the same question using a novel genotype discordant paired-sibling approach. Methods. We identified 122 sex-matched sib-pairs discordant for the Xba1 polymorphism among a new set of 743 Finnish subjects from 227 families with Type II diabetes and paired analyses were done by McNemar test of symmetry and by permutation tests. Results. Paired analysis showed that siblings with the A2 variant had more hypertension (p = 0.0067), obesity (p = 0.033) and microalbuminuria (p = 0.031) but not significantly more Type II diabetes (p = 0.27) than siblings with the A1 variant. Siblings with the A2 variant were more often treated by insulin (p = 0.050) or anti-hypertensive medication (p = 0.0060) or both. Diabetic A2 variant carriers had higher triglyceride (p = 0.023) and lower HDL cholesterol (p = 0.0059) concentrations and an earlier age at onset of diabetes (p = 0.022) than diabetic siblings with the A1 variant. In non-diabetic sib-pairs the presence of the A2 variant was associated with higher diastolic (p = 0.0014) blood pressure. Finally, the allele frequency of the XbaI polymorphism differed between 216 randomly chosen unrelated Type II diabetic patients and 115 unrelated healthy control spouses without a family history of Type II diabetes (12.7 vs. 6.5 %, p = 0.013). Conclusion/interpretation. The A2 allele of the XbaI polymorphism in the GYS1 confers an increased susceptibility to different features of the metabolic syndrome and Type II diabetes. [Diabetologia (1999) 42: 1138–1145]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051282
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  • 2
    Electronic Resource
    Electronic Resource
    Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state (2000)
    Springer
    Diabetologia 43 (2000), S. 1476-1483 
    Details
    ISSN: 1432-0428
    Keywords: Keywords LADA ; MODY ; Type II diabetes ; IGT ; insulin secretion ; insulin sensitivity.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. To evaluate insulin sensitivity and insulin secretion in prediabetic and diabetic subjects with mutations in MODY1 (HNF-4α) and MODY3 (HNF-1α) genes, in subjects with GAD antibodies, latent autoimmune diabetes in adults and in subjects with the common form of Type II (non-insulin-dependent) diabetes mellitus. Methods. Insulin secretion was measured as the incremental 30-min insulin (I30) and insulin glucose ratio (I:G30) during OGTT whereas insulin sensitivity was measured as the insulin sensitivity index during OGTT in 131 carriers of MODY mutations [NGT = 38, IFG/IGT = 21, diabetes mellitus (DM) = 72], in 293 subjects with GADA (NGT = 47, IFG/IGT = 29, DM = 217) and in 2961 subjects with a family history of the common form of Type II diabetes but without MODY mutations or GADA (NGT = 1360, IFG/IGT = 857, DM = 744). A subgroup of the subjects underwent a euglycaemic clamp (n = 210) and intravenous glucose tolerance test (n = 337) for the estimation of insulin sensitivity and first-phase insulin secretion. Results. Non-diabetic subjects with MODY mutations had pronounced impaired insulin secretion (I30, I:G30) compared with the two other groups (p = 0.005). Normal or non-diabetic glucose tolerance was maintained by enhanced insulin sensitivity compared with the other two groups (p 〈 0.05 and p 〈 0.005). In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes. The 2-h glucose values inversely correlated with insulin sensitivity in subjects with GADA (r = –0.447, p 〈 0.001) and subjects from Type II diabetic families (r = –0.426, p 〈 0.001), whereas no such relation was observed in subjects with MODY mutations (r = 0.151, p = NS). There were no statistically significant differences in insulin secretion or insulin sensitivity between subjects with GADA or subjects with a family history of Type II diabetes, either at the NGT or the IFG/IGT stage. Conclusion/interpretation. Glucose-tolerant carriers of MODY mutations are characterised by a severe impairment in insulin secretion. Enhanced insulin sensitivity is the most likely explanation for the normal glucose tolerance. Whereas subjects with positive GADA or Type II diabetes have impaired insulin sensitivity with increasing glucose concentrations, MODY mutation carriers seem to be protected from the effect of glucose toxicity. [Diabetologia (2000) 43: 1476–1483]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051558
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of the combination of insulin and glibenclamide in Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents (1988)
    Springer
    Diabetologia 31 (1988), S. 206-213 
    Details
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes ; insulin treatment ; sulfonylurea ; secondary failure ; glibenclamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of combined insulin and sulfonylurea therapy on glycaemic control and B-cell function was studied in 15 Type 2 (non-insulin-dependent) diabetic patients who had failed on treatment with oral hypoglycaemic agents. The patients were first treated with insulin alone for four months. Five patients were given two daily insulin doses and ten patients one dose. During insulin treatment the fasting plasma glucose fell from 14.5±0.8 to 8.8±0.4 mmol/l and the HbA1 concentration from 12.6±0.4 to 9.2±0.2%. This improvement of glycaemic control was associated with a suppression of basal (from 0.31±0.04 to 0.10±0.02 nmol/l) and glucagon-stimulated (from 0.50±0.08 to 0.19±0.04 nmol/l) C-peptide concentrations. Four months after starting insulin therapy the patients were randomised to a four-month double-blind cross-over treatment with insulin combined with either 15 mg glibenclamide per day or with placebo. Addition of glibenclamide to insulin resulted in a further reduction of the fasting plasma glucose (7.9±0.5 mmol/l) and HbA1 (8.3±0.2%) concentration whereas the basal (0.21±0.03 nmol/l) and glucagon-stimulated C-peptide concentrations (0.34±0.06 nmol/l) increased again. Addition of placebo to insulin had no effect. The daily insulin dose could be reduced by 25% after addition of glibenclamide to insulin, while it remained unchanged when insulin was combined with placebo. The fasting free insulin concentration did not differ between the glibenclamide and placebo periods (28±6 vs 30±5 mmol/l). The fasting free insulin concentration correlated, however, positively with the insulin dose (r=0.76, p〈0.01) indicating that the insulin dose was the main determinant of the free insulin concentration. In contrast, the basal C-peptide concentration was higher during the insulin plus glibenclamide than during the insulin plus placebo period (0.21±0.03 vs 0.16±0.03 nmol/l; p〈0.05). Addition of glibenclamide to insulin therapy increased the treatment cost by 30–50%, was associated with increased frequency of mild hypoglycaemic reactions and with a slight, but significant fall in HDL cholesterol concentration (from 1.40±0.07 to 1.29±0.06; p〈0.05) compared with insulin plus placebo. We conclude that in Type 2 diabetic patients, who have failed on treatment with oral hypoglycaemic agents, the combination of insulin and glibenclamide resulted in slightly improved glycaemic control and allowed reduction of the insulin dose. The price for this improvement was higher treatment costs, more (mild) hypoglycaemic reactions and a marginal fall in the HDL cholesterol concentration. Whether the same effect could have been achieved with divided insulin doses in all patients is not known.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00290586
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  • 4
    Electronic Resource
    Electronic Resource
    Modulation of hepatic glucose production by non-esterified fatty acids in Type 2 (non-insulin-dependent) diabetes mellitus (1991)
    Springer
    Diabetologia 34 (1991), S. 409-415 
    Details
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes ; hepatic glucose production ; insulin resistance ; non-esterified fatty acids ; nicotinic acid derivative
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To study the effect of changes in plasma non-esterified fatty acid concentration on suppression of hepatic glucose production by insulin eight Type 2 (non-insulin-dependent) diabetic patients participated in three euglycaemic, hyperinsulinaemic (108pmol · m2−1 · min−1) clamp studies combined with indirect calorimetry and infusion of [3-3H]-glucose and [1-14C]palmitate; (1) a control experiment with infusion of NaCl 154 mmol/l, (2) heparin was infused together with insulin, and (3) an antilipolytic agent, Acipimox, was administered at the beginning of the experiment. Six healthy volunteers participated in the control experiment. Plasma non-esterified fatty acid concentrations during the insulin clamp were in diabetic patients: (1) 151±36 μmol/1, (2) 949±178 μmol/l, and (3) 65±9 μmol/l; in healthy control subjects 93±13 μmol/l. Non-esterified fatty acid transport rate, oxidation and non-oxidative metabolism were significantly higher during the heparin than during the Acipimox experiment (p〈0.001). Suppression of hepatic glucose production by insulin was impaired in the diabetic compared to control subjects (255±42 vs 51±29 μmol/min, p〈0.01). Infusion of heparin did not affect the suppression of hepatic glucose production by insulin (231±49 μmol/min), whereas Acipimox significantly enhanced the suppression (21±53 μmol/min, p〈0.001 vs 154 mmol/l NaCl experiment). We conclude that insulin-mediated suppression of hepatic glucose production is not affected by increased non-esterified fatty acid availability. In contrast, decreased non-esterified fatty acid availability enhances the suppression of hepatic glucose production by insulin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00403179
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  • 5
    Electronic Resource
    Electronic Resource
    High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes (1999)
    Springer
    Diabetologia 42 (1999), S. 1131-1137 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Glucokinase ; HNF-1 ; HNF-4 ; MODY ; MIDD ; genetics.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. To investigate the contribution of mutations in maturity-onset diabetes of the young (MODY) and mitochondrial genes to early-onset diabetes with a strong family history of diabetes in a cohort with a high prevalence of Type I (insulin-dependent) diabetes mellitus. Methods. Screening for sequence variants in the hepatocyte nuclear factor (HNF)–4 α (MODY1), glucokinase (MODY2), HNF-1 α (MODY3) genes and mitochondrial DNA was carried out in 115 Finnish and Swedish patients with early-onset ( ≤ 40 years) diabetes using the single strand conformation polymorphism (SSCP) technique and direct sequencing. Allele frequencies were compared with 118 patients with onset of diabetes Type II (non-insulin-dependent) diabetes mellitus after the age of 40 and 92 non–diabetic control subjects without a family history of diabetes. Results. In total 52 sequence variants were found in the HNF-1α, HNF-4α and glucokinase genes, 12 of which were considered as MODY mutations. Three families had the A3243G mutation in the mitochondrial tRNA Leu gene, which resulted in an overall prevalence of these mutations of 13 %. Conclusion/interpretation. Among 115 Scandinavian families, mutations in the HNF-1α gene represented the most common cause of familial early-onset ( ≤ 40 years) diabetes: MODY3 (5.2 %) more than MODY2 (3.5 %) more than MIDD (2.6 %) more than MODY1 (1.7 %). [Diabetologia (1999) 42: 1131–1137]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051281
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  • 6
    Electronic Resource
    Electronic Resource
    Metabolic characteristics of autoimmune diabetes mellitus in adults (1991)
    Springer
    Diabetologia 34 (1991), S. 46-51 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; Type 2 (non-insulin-dependent) diabetes ; islet cell antibodies ; glucose metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It is still a matter of debate whether patients who develop islet-cell antibody positive autoimmune diabetes during adulthood represent slowly evolving Type 1 (insulindependent) diabetes mellitus or a separate subgroup of Type 2 (non-insulin-dependent) diabetes. To address this question, we measured C-peptide response to a test meal, and energy metabolism in the basal state and during a euglycaemic, hyperinsulinaemic clamp in (1) 29 patients with Type 2 diabetes; (2) 10 patients with autoimmune diabetes developing after the age of 40 years; (3) 11 patients with Type 1 diabetes and (4) 15 non-diabetic control subjects. While C-peptide response to a test meal was lacking in Type 1 diabetes and nearly normal in Type 2 diabetes, the C-peptide response in autoimmune diabetes was markedly reduced. Patients with Type 2 diabetes, autoimmune diabetes and Type 1 diabetes showed a 47%, 45% and 42%, respectively, reduction in the rate of non-oxidative glucose metabolism compared with control subjects (p〈0.05-0.01). Similarly, patients with Type 2 diabetes (+52%), autoimmune diabetes (+27%) and Type 1 diabetes (+33%) presented with an enhanced basal rate of hepatic glucose production, which was less suppressed by insulin compared with healthy control subjects (p〈0.01). However, patients with autoimmune diabetes derived more energy from oxidation of glucose and proteins and less energy from oxidation of lipids than patients with either Type 1 or Type 2 diabetes (p〈0.05-0.01). In conclusion, patients who develop autoimmune diabetes during adulthood share the defects in hepatic glucose production and in non-oxidative glucose metabolism with both Type 1 and Type 2 diabetes. Oxidative energy metabolism in autoimmune diabetes, however, differs from that observed in Type 1 and Type 2 diabetes. Given the metabolic characteristics of these patients, it seems justified to consider autoimmune diabetes in adults as a subgroup of diabetes developing in adult age.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00404024
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