Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNALeu(UUR) gene mutation.
ABSTRACT An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be associated with the maternally transmitted clinical phenotype of NIDDM and sensorineural hearing loss in white and Japanese pedigrees. We have detected this mutation in 25 of 50 tested members of five white French pedigrees. Affected (mutation-positive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The present report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in seven mutation-positive individuals who have a range of glucose tolerance from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin secretion was evaluated during two experimental protocols: the first involved the measurement of insulin secretory responses during intravenous glucose tolerance test, hyperglycemic clamp, and intravenous injection of arginine. The second consisted of the administration of graded and oscillatory infusions of glucose and studies to define C-peptide kinetics. This protocol was aimed at assessing two sensitive measures of beta-cell dysfunction: the priming effect of glucose on the glucose-insulin secretion rate (ISR) dose-response curve and the ability of oscillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of between- and within-subject variability. However, all subjects, including those with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tolerance, glucose failed to prime the ISR response, entrainment of ultradian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subjects with overt diabetes. In conclusion, the pathophysiological mechanisms responsible for the development of NIDDM and insulin-requiring diabetes in this syndrome are complex and might include defects in insulin production, glucose toxicity, and insulin resistance. However, our data suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosphorylation and implicate the glucose-sensing mechanism of beta-cells.
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ABSTRACT: Rhythms govern many endocrine functions. Examples of such rhythmic systems include the insulin-secreting pancreatic beta-cell, which regulates blood glucose, and the gonadotropin-releasing hormone (GnRH) neuron, which governs reproductive function. Although serving very different functions within the body, these cell types share many important features. Both GnRH neurons and beta-cells, for instance, are hypothesized to generate at least two rhythms endogenously: (1) a burst firing electrical rhythm and (2) a slower rhythm involving metabolic or other intracellular processes. This review discusses the importance of hormone rhythms to both physiology and disease and compares and contrasts the rhythms generated by each system.Endocrine 03/2014; · 3.53 Impact Factor
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ABSTRACT: A prospective, randomized, double-blind, placebo-controlled study S erum IGF-I is reduced in adoles-cents with type 1 diabetes, and in-jections of IGF-I improve glycemic control (1). The fact that sulfonylureas can increase IGF-I directly and indepen-dent of insulin has not been included in standard literature (2). The first observa-tion of a stimulatory effect on serum IGF-I was made in hypophysectomized rats (3). In in vitro experiments, glibenclamide stimulated growth of human chondro-cytes via IGF-I and independent of insulin (4). Glibenclamide and glimepiride had dose-dependent stimulatory effects on IGF-I transcription and production in hu-man liver cells (HuH7) (5). We recruited 40 pubertal patients with type 1 diabetes of a duration of 1 year (negative for C-peptide) at Ulm (n 20) and Bern (n 20). They were ran-domly allocated at the start of treatment and each participant underwent a 6-week course of either glimepiride (one daily dose of 8.2 mol 4 mg; n 20) or placebo (n 20) in addition to the mul-tiple injection intensive insulin therapy (Table 1). One patient receiving glimepi-ride was withdrawn because of viral en-cephalitis. The primary end point in our study had been defined as the increment of IGF-I between start of treatment and 6 – 8 weeks thereafter. Assuming a SD of 200 ng/ml, we estimated that in a two-sided statistical test with an level of 0.05 and a power of 80%, sample sizes of 17 patients per group would be sufficient to attain a significant result, if a true rise in IGF-I from 300 ng/ml (5th percentile) to 500 ng/ml (50th percentile) occurred. The study protocol was approved by the local ethics committees at both centers. At the time of allocation, both groups were not relevantly different regarding age, sex, weight, height, blood pressure, insulin dose, fasting serum glucose, hypo-glycemic events, IGF-I, IGF binding pro-tein-3 (IGFBP-3), HbA 1c , or serum lipids. No remarkable changes (Mann-Whitney U test) in IGF-I or IGFBP-3 could be ob-served during glimepiride treatment (Ta-ble 1). When compared with the placebo group, no differences could be found. Glimepiride did not influence weight, blood pressure, insulin dosage, fasting serum glucose, rate of hypoglycemias, HbA 1c , or serum lipids. In adolescents with type 1 diabetes, the peripheral mode of application of in-sulin is likely to lead to IGF-I insuffi-ciency, consecutively to growth hormone hypersecretion and an insulin-resistant state. In case oral sulfonylureas could effectively increase IGF-I, they could pre-sent a suitable therapeutic option because they are inexpensive, easy to administer, and do not endanger patients by hypogly-cemias. An increase of IGF-I to the upper normal range would be desirable and would not likely be associated with severe side effects (6). For safety reasons, glimepiride, which exhibited a higher stimulatory ef-fect on IGF-I than glibenclamide (5), was given at a usual dose. We anticipated that a treatment duration of 6 weeks should be sufficient to induce a change in IGF-I. The reason why IGF-I did not increase signif-icantly probably lies in the low serum concentrations of glimepiride (median 0.16 mol/l) achieved with our protocol. Glimepiride levels were up to four times higher in the cell culture experiments (5). The authors consider it appropriate to suggest further studies using higher con-centrations of sulfonylureas.
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ABSTRACT: The m.3243A>G mutation in the mitochondrial gene MT-TL1 leads to a wide clinical spectrum ranging from asymptomatic carriers to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) at the severe end. Diabetes mellitus (DM) occurs in mitochondrial diseases, with the m.3243A>G mutation being the most common mutation associated with mitochondrial DM. The pathogenesis of mitochondrial DM remains largely unknown, with previous studies suggesting that impaired insulin secretion is the major factor. In this study we used stable isotope infusion techniques to assess glucose metabolism in vivo and under physiological conditions in 5 diabetic and 11 non-diabetic adults with the m.3243A>G mutation and 10 healthy adult controls. Our results revealed increased glucose production due to increased gluconeogenesis in both diabetic and non-diabetic subjects with the m.3243A>G mutation. In addition, diabetic subjects demonstrated insulin resistance and relative insulin deficiency, resulting in an inability to increase glucose oxidation which can explain the development of DM in those subjects. Non-diabetic subjects showed normal insulin sensitivity; and therefore, they were able to increase their glucose oxidation rate. The ability to increase glucose utilization can act as a compensatory mechanism that explains why these subjects do not have DM despite the higher rate of glucose production. These results suggest that increased gluconeogenesis is not enough to cause DM and the occurrence of combined insulin resistance and relative insulin deficiency are needed to develop DM in individuals with the m.3243A>G mutation. Therefore, multiple defects in insulin and glucose metabolism are required for DM to occur in individuals with mitochondrial diseases. The results of this study uncovers previously undocumented alterations in glucose metabolism in individuals with the m.3243A>G mutation that contribute significantly to our understanding of the pathogenesis of mitochondrial DM and can have significant implications for its management.Mitochondrion 07/2014; · 3.52 Impact Factor