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Hyperproinsulinemia Is Not a Characteristic Feature in the Offspring of Patients with Different Phenotypes of Type II Diabetes

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Hyperproinsulinemia Is Not a Characteristic Feature in the Offspring of Patients with Different Phenotypes of Type II Diabetes European Journal of Endocrinology (2000) 143 251±260 ISSN 0804-4643 CLINICAL STUDY Hyperproinsulinemia is not a characteristic feature in the offspring of patients with different phenotypes of type II diabetes Ilkka K J Vauhkonen1, Leo K Niskanen1, Leena MykkaÈnen3, Steven M Haffner3, Matti I J Uusitupa2 and Markku Laakso1 Departments of 1Medicine and 2Clinical Nutrition, Kuopio University Hospital and University of Kuopio, Kuopio, Finland, and 3Department of Medicine/Division of Clinical Epidemiology, University of Texas, San Antonio, Texas, USA (Correspondence should be addressed to M Laakso, Department of Medicine, University of Kuopio, FIN-70210 Kuopio, Finland; Fax: +358-17-173993) Abstract Objective: The purpose of this work was to study whether there are differences in plasma proinsulin levels and proinsulin-to-speci®c insulin ratio in the offspring of patients with different phenotypes of type II diabetes. Design: Eleven glucose-tolerant offspring of type II diabetic patients with de®cient insulin secretion phenotype (IS group), nine glucose-tolerant offspring of patients with insulin-resistant phenotype (IR group), and fourteen healthy control subjects without a family history of diabetes were studied. Methods: Plasma speci®c insulin, plasma proinsulin, and plasma C-peptide levels were measured during a 2-h oral glucose tolerance test and during hyperglycemic clamp. Results: Plasma proinsulin levels during the oral glucose tolerance test and the hyperglycemic clamp did not differ among the study groups. The IR group had a lower fasting plasma proinsulin-to-speci®c insulin ratio (10.3 6 1.7%) than the control group (15.4 6 1.4%; P < 0.05) and the IS group (18.6 6 2.7%; P < 0.05). Furthermore, the IR group had lower plasma proinsulin-to-speci®c insulin ratio at 30, 60 and 90 min after the oral glucose load than the IS group. However, there were no signi®cant differences in proinsulin-to-C-peptide ratio during the oral glucose tolerance test among the study groups. In stepwise multiple regression analysis, hepatic speci®c insulin extraction in the fasting state (b 0.65; P < 0.001) and fasting blood glucose (b 0.32; P < 0.05) together explained 52% of the variation in fasting plasma proinsulin-to-speci®c insulin ratio. Conclusions: Hyperproinsulinemia is not a characteristic ®nding in glucose-tolerant offspring of type II diabetic probands with de®cient insulin secretion or insulin-resistant phenotype. The differences in proinsulin-to-speci®c insulin ratios were most likely explained by different hepatic extraction among the study groups. European Journal of Endocrinology 143 251±260 Introduction Alternatively, other studies have suggested that hyper- proinsulinemia is a secondary defect in subjects devel- Hyperproinsulinemia is commonly present in type II oping type II diabetes, and could be due to increased diabetes (1±10) and according to most studies also in demand placed on the b cell by hyperglycemia and/or subjects with impaired glucose tolerance (7±12). The insulin resistance (7±8, 18). Because insulin-resistant reasons for hyperproinsulinemia are, however, still individuals often have hyperinsulinemia, it is not clear unknown but several explanations have been proposed whether hyperproinsulinemia per se is a marker of b cell (13). Hyperproinsulinemia could be due to a primary distress. Therefore, disproportionally increased serum defect in the b cell, leading to increased secretion of concentrations of proinsulin relative to insulin may be incompletely processed insulin precursors, i.e. impaired a surrogate marker of the failing pancreas (4), a phe- proinsulin processing. Indeed, in some individuals, nomenon which has been reported in subjects with hyperproinsulinemia has been shown to be present impaired glucose tolerance (8, 11, 19). However, the without hyperglycemia (14±17), suggesting that an response of the normal b cell to increased demand impairment in proinsulin processing could represent has been hypothesized to result in enhanced processing an early defect in the development of type II diabetes. of proinsulin into insulin (4). Insulin resistance has, q 2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 10/02/2021 04:21:55AM via free access 252 I K J Vauhkonen and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2000) 143 indeed, been associated with low proinsulin-to-insulin The formation of the study population for the present ratio in normoglycemic subjects (20), whereas the study study has been described in more detail elsewhere (24). by Wang et al. (21) could not ®nd this association. Brie¯y, three groups of subjects were studied. However, no previous study has taken into account the variations in hepatic extraction of insulin. Offspring of the probands with de®cient insulin Previous studies aiming to investigate the role of secretion phenotype (IS group) Originally, the IS hyperproinsulinemia as an early defect in type II dia- group consisted of twenty subjects (®fteen women and betes have included individuals at high risk of develop- ®ve men) (24). The nine subjects with impaired glucose ing type II diabetes, i.e. the ®rst-degree relatives of tolerance were excluded. Thus the IS group for the patients with type II diabetes (9, 14, 16, 22). However, present study comprised eleven glucose-tolerant sub- these studies have given contradictory results. Three jects who were offspring of eight probands. studies have shown that the ®rst-degree relatives of type II diabetic patients have elevated proinsulin levels Offspring of the probands with insulin-resistant (14, 16, 22), whereas in one study parental diabetes phenotype (IR group) Originally, the IR group was related neither to fasting proinsulin levels nor to consisted of eighteen subjects (eleven women and proinsulin-to-insulin ratio (9). As type II diabetes is a seven men) (24). Likewise, the subjects with impaired heterogenous disorder (23), the contradictory results glucose tolerance (nine subjects) were excluded. Thus in previous studies may be due to different phenotypes the glucose-tolerant subjects of the IR group (nine of type II diabetes in the probands. We have recently subjects) were included in the present study and they shown that defects in insulin secretion and insulin were offspring of six probands. action are inherited, and either of them could represent primary defects in the development of type II diabetes Control group The control subjects for the present (24). study were offspring of control subjects with repeatedly The aim of this study was to examine whether there normal glucose tolerance according to the World are differences in proinsulin levels or in proinsulin-to- Health Organization criteria (29) determined by an speci®c insulin ratio between the glucose-tolerant off- OGTT (baseline, 5 years and 10 years) in the same spring of patients with de®cient insulin secretion follow-up study (25±28). The control subjects had to phenotype and insulin-resistant phenotype of type II ful®l the following inclusion criteria: (i) age from 30 diabetes and, furthermore, whether hyperproinsuline- to 55 years; (ii) no diabetes; (iii) ®rst-degree relatives mia re¯ects an early defect in the pathogenesis of type without a history of diabetes; (iv) no drug treatment II diabetes. nor any disease that could potentially disturb carbo- hydrate metabolism; (v) body mass index (BMI) within the range of means 6 2 S.D. of the BMI in the IS and IR Subjects and methods groups; and (vi) no history of hypertension. The control group consisted of fourteen glucose-tolerant offspring Subjects (®ve men and nine women) of eight probands. The subjects for the present study were offspring of the patients with newly diagnosed type II diabetes who Characteristics of the probands at the 10-year were originally studied in 1979±81 (25±28). We have follow-up study The probands with de®cient insulin followed these patients for over 10 years and performed secretion phenotype had mean age of 67.4 years, repeated oral glucose tolerance tests (OGTT) (baseline, mean BMI of 26.7 kg/m2, mean fasting C-peptide 5 years and 10 years). The probands were subdivided of 335 pmol/l and mean fasting blood glucose of into two groups on the basis of fasting C-peptide values 13.6 mmol/l. One proband was treated with diet at the 10-year follow-up study: (i) type II diabetic alone, four probands with oral hypoglycemic agents patients with low fasting C-peptide level (<450 pmol/l) and three probands with insulin. The mean age of re¯ecting de®cient insulin secretion capacity and the probands with insulin-resistant phenotype was 66.7 (ii) type II diabetic patients with high fasting C-peptide years, their mean BMI was 34.7 kg/m2, their mean level (>880 pmol/l) re¯ecting insulin resistance. Pro- fasting plasma C-peptide was 951 pmol/l and their bands with glutamic acid decarboxylase and/or islet mean fasting blood glucose was 11.7 mmol/l. Three cell antibody positivity (eleven patients altogether) probands were treated with diet alone, three probands were excluded. Additional exclusion criteria for the with oral hypoglycemic agents and none was receiving selection of the offspring were: (i) diabetes mellitus insulin treatment. The probands with the insulin- in both parents or in the offspring; (ii) dyslipidemia resistant phenotype had higher fasting C-peptide con- (serum total triglycerides >2.5 mmol/l); (iii) drug centration even after correction for age, BMI and treatment or any disease that could potentially disturb fasting blood glucose concentration. The probands of carbohydrate metabolism; (iv) pregnancy; (v) overt the control subjects had a mean age of 64.7 years, mean psychiatric disease; and (vi) under 30 or over 55 years BMI of 26.0 kg/m2, mean fasting plasma C-peptide of of age. 480 pmol/l and mean blood glucose of 5.1 mmol/l.
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