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Leif Groop and Risto Pelkonen

ABSTRACT. Secondary failure is a common problem in the treatment of patients with type II diabetes. The underlying mechanisms are reviewed, and special interest is focused on the assessment of insulin secretion and insulin sensitivity. Impaired beta-cell function seems to be the major cause of secondary drug failure in patients with normal weight, whereas insulin resistance is of greater importance in obese patients. The importance of Cpeptide determinations to detect patients needing insulin is emphasized. The concept of progressive deterioration of beta-cell function with time in type II diabetes is challenged.

Different treatment modalities for the management of patients with secondary drug failure are discussed and special interest is focused on the combination of insulin and sulfonylureas in the management of secondary failure patients with slightly impaired insulin secretion.

Key words: secondary drug failure, type II diabetes, Cpeptide, insulin sensitivity, oral antidiabetic drugs, insulin therapy.

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Leif Groop and Karl Johan Tötterman

Abstract.

In a double-blind cross-over trial we compared the effects of placebo and propranolol on iv tolbutamide and oral glipizide-stimulated insulin secretion in 10 noninsulin dependent diabetics. The patients were randomly allocated for 2 weeks treatment with placebo and propranolol 80 mg twice daily. At the end of each period an iv tolbutamide test and an oral glipizide-glucose-test were performed.

Tolbutamide-stimulated insulin secretion was not affected by propranolol. There was no change in blood glucose levels during the iv tolbutamide test (IVTT), which excluded an effect of blood glucose on insulin secretion.

During the oral glipizide-glucose challenge propranolol decreased blood glucose at 60 min (P < 0.01) and increased C-peptide at 0 min (P < 0.01) and 30 min (P < 0.05) compared with placebo.

In contrast to earlier results obtained in animals and healthy subjects propranolol does not inhibit insulin- or C-peptide responses to sulphonylurea in patients with non-insulin dependent diabetes mellitus.

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Leif Groop and Esa-Matti Tolppanen

Abstract. This study was designed to evaluate the influence of age, duration of diabetes, relative body weight and glycaemic control on beta-cell function and insulin sensitivity in 250 patients with onset of nonketotic diabetes between the age of 35 and 70 years (Type 2 diabetes). Beta-cell function was assessed by measuring serum C-peptide concentrations after I mg of glucagon iv. It was not influenced by age, age at onset of diabetes nor by the duration of the disease. This suggests that progressive deterioration of beta-cell function with time is not a consistent finding in Type 2 diabetes. Insulin sensitivity, measured as the glucose disappearance rate, KITT, in response to iv-insulin, was not significantly influenced by age or age at onset, but decreased consistently with the duration of the disease (P < 0.001). Beta-cell function was not correlated to fasting blood glucose and HbA1 concentrations. In contrast, there was a strong inverse relationship between glycaemic control and insulin sensitivity (P < 0.001) indicating that decreased insulin sensitivity contributes to poor glycaemic control in these patients. Attempts to improve glycaemic control in patients with Type 2 diabetes should therefore include means to improve insulin sensitivity.

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Per-Henrik Groop, Leif Groop, Karl Johan Tötterman and Frej Fyhrquist

Abstract. The relationship between changes in gastric inhibitory polypeptide (GIP), C-peptide and insulin responses to meals was studied in 8 normal subjects after 2 weeks of Acarbose treatment. Acarbose caused a significant reduction of GIP and insulin responses (P <0.05). The decrease in insulin response could not be explained by changes in the glycaemic stimulus of insulin secretion, as Acarbose did not significantly change the plasma glucose response to meals during the study. The reduced insulin response was seen without a concomitant reduction in the C-peptide response to the meals, thus resulting in a decreased insulin/C-peptide ratio after Acarbose treatment (P < 0.05). The changes in GIP response after Acarbose correlated positively with the change in insulin/C-peptide ratio (r = 0.69; P < 0.05). Our data thus challenge the concept that Acarbose therapy affects the secretion of insulin. The positive relationship between changes in GIP response and changes in the insulin/C-peptide ratio rather suggests that GIP affects the metabolism of insulin or C-peptide.

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Leif Groop, Kari Harno and Esa-Matti Tolppanen

Abstract. Thirteen patients (6 females and 7 males) who were secondary failures on oral drug therapy were randomly allocated to either 2 months of treatment with insulin + glibenclamide or insulin + placebo. Thereafter the treatment schedules of the two groups were switched over for another two months.

The combination of insulin and glibenclamide was more effective in lowering the fasting blood glucose (P = 0.026) and 24 h urine glucose (P = 0.042) than the combination of insulin and placebo. The combination therapy with insulin and glibenclamide revealed higher basal (P = 0.021) and glucagon-stimulated C-peptide concentrations (P = 0.037) than therapy with insulin and placebo. However, insulin binding to erythrocytes did not differ between the two study periods. The results indicate that the addition of glibenclamide to insulin in type II diabetics poorly controlled by oral antidiabetics alone may slightly improve diabetic control. The mechanism of this action is due at least partly to sulphonylureainduced stimulation of endogenous insulin secretion.

The effectiveness of the combination treatment during long-term therapy still remains to be proven, however.

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Anja I Franssila-Kallunki, Johan G Eriksson and Leif C Groop

The present study was undertaken to compare the effect of hyperglycemia and euglycemia during identical hyperinsulinemic conditions on glucose metabolism in NIDDM subjects. Eight NIDDM subjects participated in a 4 h hyperglycemic (12.1±0.7 mmol/l), hyperinsulinemic (475±43 pmol/l) and in a 4 h euglycemic (5.5±0.5 mmol/l), hyperinsulinemic (468±36 pmol/l) insulin clamp in combination with indirect calorimetry and [3H]-3-glucose. Six non-diabetic subjects were studied during euglycemia (5.1±0.2 mmol/l) and hyperinsulinemia (474±35 pmol/l) and served as controls. In NIDDM patients the rate of insulin-stimulated glucose disposal was 57% greater during hyperglycemia compared with euglycemia throughout the 4 h clamp (p<0.01). The major part of the increase in glucose metabolism during hyperglycemia was due to an increase in the non-oxidative glucose metabolism (89%). Whereas glucose metabolism could not be normalized during the prolonged euglycemic hyperinsulinemic clamp in NIDDM patients (49.9±6.8 vs 57.5±5.4 μmol·(kgLBM)−1·min−1 in controls) the addition of hyperglycemia resulted in complete normalization of the glucose disposal rates (78.3±5.8 μmol·(kgLBM)−1·min−1). The effect of hyperglycemia was apparent already at 60 min of the clamp. The data thus suggest that glucose metabolism in NIDDM is insulin resistant, but that the defect in insulin-stimulated glucose uptake can be overcome by increasing the glucose concentration.

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Anders H Olsson, Tina Rönn, Claes Ladenvall, Hemang Parikh, Bo Isomaa, Leif Groop and Charlotte Ling

Context

Mitochondrial ATP production is important in the regulation of glucose-stimulated insulin secretion. Genetic factors may modulate the capacity of the β-cells to secrete insulin and thereby contribute to the risk of type 2 diabetes.

Objective

The aim of this study was to identify genetic loci in or adjacent to nuclear-encoded genes of the oxidative phosphorylation (OXPHOS) pathway that are associated with insulin secretion in vivo.

Design and methods

To find polymorphisms associated with glucose-stimulated insulin secretion, data from a genome-wide association study (GWAS) of 1467 non-diabetic individuals, including the Diabetes Genetic Initiative (DGI), was examined. A total of 413 single nucleotide polymorphisms with a minor allele frequency ≥0.05 located in or adjacent to 76 OXPHOS genes were included in the DGI GWAS. A more extensive population-based study of 4323 non-diabetics, the PPP-Botnia, was used as a replication cohort. Insulinogenic index during an oral glucose tolerance test was used as a surrogate marker of glucose-stimulated insulin secretion. Multivariate linear regression analyses were used to test genotype–phenotype associations.

Results

Two common variants were identified in the DGI, where the major C-allele of rs606164, adjacent to NADH dehydrogenase (ubiquinone) 1 subunit C2 (NDUFC2), and the minor G-allele of rs1323070, adjacent to cytochrome c oxidase subunit VIIa polypeptide 2 (COX7A2), showed nominal associations with decreased glucose-stimulated insulin secretion (P=0.0009, respective P=0.003). These associations were replicated in PPP-Botnia (P=0.002 and P=0.05).

Conclusion

Our study shows that genetic variation near genes involved in OXPHOS may influence glucose-stimulated insulin secretion in vivo.

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Elisabeth IM Widén, Johan G Eriksson, Agneta V Ekstrand and Leif C Groop

A possible pathogenetic link between absence of first-phase insulin secretion and development of impaired glucose metabolism has been suggested by the results of several cross-sectional studies. First-phase insulin secretion measured during a + 7 mmol/l hyperglycemic glucose clamp correlated with total glucose disposal during the clamp (r = 0.65, p <0.001, N = 59). To examine whether restoration of first-phase insulin secretion improves peripheral glucose uptake in subjects with impaired glucose utilization, seven insulin-resistant subjects (age 54 (38–62) years; BMI 29.3 (21.7–35.8); fasting plasma glucose 5.5 (4.8–7.2) mmol/l; fasting insulin 57 (37–105) pmol/l with impaired first-phase (148 (29–587) vs controls 485 (326–1086) pmol/l× 10 min; p<0.05) and normal second-phase (1604 (777–4480) vs controls (1799 (763–2771) pmol/l × 110 min) insulin secretion were restudied. The impaired first-phase insulin secretion was restored by an iv insulin bolus at the start of the hyperglycemic clamp. Substrate oxidation rates and hepatic glucose production were determined by indirect calorimetry and [3-3H]glucose infusion. Total glucose uptake was impaired in the insulinresistant subjects with impaired first-phase insulin secretion compared to controls (18.8 (13.2–22.2) vs 34.8 (24.3–62.1) μmol·kg−1·min−1; p<0.01). Restoration of first-phase insulin secretion (1467 (746–2440) pmol/l× 10 min) did not affect glucose uptake (20.2 (9.9–23.8) μmol·kg−1·min−1), with no difference in oxidative and non-oxidative glucose metabolism between the experiments. Second-phase insulin secretion was similar during both experiments. We conclude that although first-phase insulin secretion correlates with total glucose uptake, replacement of impaired first-phase insulin secretion does not improve glucose uptake in subjects with impaired glucose disposal and normal second-phase insulin secretion. The data dispute a causal relationship between first-phase insulin secretion and impaired glucose uptake in these subjects.

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Mette K Andersen, Virve Lundgren, Bo Isomaa, Leif Groop and Tiinamaija Tuomi

Objective

Previously, we observed an association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. The aims of this study were to assess whether type 1 diabetes susceptibility gene variants explain this association and investigate the effect of the variants on insulin secretion and presence of glutamic acid decarboxylase autoantibodies (GADA) in nondiabetic adults.

Design and methods

Polymorphisms in INS (rs689), PTPN22 (rs2476601), CTLA4 (rs3087243), and the HLA-DQA1-DQB1 regions (rs2187668 and rs7454108 tagging HLA-DQ2.5 and HLA-DQ8 respectively) were genotyped in the Botnia Prospective Study (n=2764), in which initially nondiabetic participants were followed for a mean of 8.1 years.

Results

The variants did not explain the association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. In these nondiabetic adults, HLA-DQ and PTPN22 risk genotypes were associated with GADA (HLA-DQ2.5/HLA-DQ8 or HLA-DQ8: OR (95% CI): 1.7 (1.3–2.3), P=0.0004; PTPN22 CT/TT: OR: 1.6 (1.2–2.2), P=0.003; P values were adjusted for sex, age, BMI, and follow-up time). A higher genetic risk score was associated with lower insulin secretion (insulinogenic index: 13.27 (16.27) vs 12.69 (15.27) vs 10.98 (13.06), P=0.02) and better insulin sensitivity index (risk score of 0–1 vs 2–3 vs 4–6: 142 (111) vs 144 (118) vs 157 (127), P=0.01) at baseline and a poorer capacity to compensate for the increased insulin demand after follow-up.

Conclusions

In nondiabetic adults, HLA-DQ2.5/HLA-DQ8 and PTPN22 CT/TT genotypes were associated with GADA.

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Leif C. Groop, Riccardo Bonadonna, Stefano DelPrato, Klaus Ratheiser and Ralph A. DeFronzo

Abstract.

The effect on energy metabolism of a 6-h prolongation of the conventional 12-h overnight fast was examined in 9 healthy subjects and in 7 patients with non-insulin-dependent diabetes mellitus. Plasma glucose concentration decreased by 7 and 23%, in control and diabetic subjects, respectively. In control subjects, the fall in plasma glucose was associated with a slight but significant fall in plasma insulin and a rise in plasma free fatty acid concentrations. During this same period, the rates of plasma free fatty acid oxidation, measured by infusion of [14C]palmitate, and net lipid oxidation, measured by indirect calorimetry, increased in normal subjects by 55 and 76%, respectively; the rate of glucose oxidation measured by indirect calorimetry decreased by 37%. In the diabetic patients, the free fatty acid oxidation rate was enhanced already after 12 h of fasting compared with controls (2.06 vs 1.30 μmol · kg−1 · min−1; p<0.05) and did not change significantly during the 6-h observation period. After 18 h of fasting, the rate of plasma free fatty acid oxidation was similar in control and diabetic subjects. The data thus emphasize the need for strict standardization of the overnight fasting period for metabolic studies, and demonstrate the difficulties in comparing basal rates of substrate oxidation between healthy and diabetic subjects.