Mouse models of insulin resistance and type 2 diabetes.
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Adipose Tissue↗
Biomedical subjects
F Mauvais-Jarvis
Publications and source records attributed to F Mauvais-Jarvis.
[Metabolic effects of physical activity in the type 2 diabetic].
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Biological Transport↗
The polymorphism Gly574Ser in the transcription factor HNF-1alpha is not a marker of adult-onset ketosis-prone atypical diabetes in Afro-Caribbean patients.
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Adult↗
Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men.
OBJECTIVE: We investigated the effect of an intensive training program on fasting leptin and adiponectin levels. METHODS: Sixteen middle-aged men with type 2 diabetes were randomly assigned to either a training or control group. The training program consisted of 8 weeks of supervised endurance exercise (75% VO(2peak), 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO(2peak) separated by 3 min exercises at 50% VO(2peak)) once a week, on an ergocycle. RESULTS: Training decreased abdominal fat by 44%, increased mid-thigh muscle cross-sectional area by 24%, and improved insulin sensitivity by 58% without significant change in body weight. Compared with controls, no significant variation in leptin or adiponectin levels was observed. However, in the trained group, change in adiponectin correlated with change in body weight (Spearman rank correlation, r(s):-0.76, P=0.03) but not with insulin sensitivity or abdominal adiposity variations. CONCLUSIONS: An 8 week intensive training program inducing a marked reduction in abdominal fat and increase in insulin sensitivity does not affect adiponectin and leptin levels in men with type 2 diabetes.
Abdomen↗
Metabolic and immunogenetic prediction of long-term insulin remission in African patients with atypical diabetes.
AIMS: We aimed to characterize a cohort of 'atypical' diabetic patients of sub-Saharan African origin and to analyse possible determinants of long-term remission. METHODS: Over 6 years, we studied the clinical and therapeutic profile of 42 consecutive patients undiagnosed or untreated prior to inclusion presenting with cardinal features of diabetes mellitus. We measured insulin secretion and sensitivity at inclusion. Immunogenetic (anti-GAD, anti-ICA and HLA class II) markers of Type 1 diabetes were compared with a 90-non-diabetic unrelated adult African population. RESULTS: Twenty-one ketonuric patients (age 42 +/- 9 (sd) years; body mass index (BMI) 26 +/- 3 kg/m2) were initially insulin-treated (IT), and 21 non-ketonuric patients (age 38 +/- 8 years; BMI 26 +/- 5 kg/m2) had oral and/or diet therapy (NIT). Insulin could be discontinued in 47.6% (10/21) IT with adequate glycaemic control (HbA1c 6.7 +/- 1.3%), while insulin was secondarily started in 38.1% (8/21) NIT in expectation of better control. The initial basal (odds ratio (OR) 9.1, 95% confidence interval (CI) 1.3-64.4) and stimulated C-peptide (OR 8.17, 95% CI 1.5-44.1) were independently associated with remission. Insulin resistance was present in all the groups, more marked in the insulin-treated NIT. Anti-GAD antibodies and ICA were rare, but 38.1% IT vs. 1.1% controls had Type 1 diabetes HLA susceptibility haplotypes (P < 0.001) without significant difference between the subgroups. CONCLUSION: Prolonged discontinuation of insulin is frequent in African diabetic patients initially presenting with signs of insulinopenia. In our patients, long-term insulin therapy was not associated with immunogenetic markers of Type 1 diabetes. The initial measure of insulin secretion seemed a good predictor of long-term remission.
Acute Disease↗
Diabetes in Africans. Part 2: Ketosis-prone atypical diabetes mellitus.
Diabetes is increasing with ageing and changes in lifestyle in populations of African ancestry as described in the first part of this review. Apart from classical type 1 and Type 2 diabetes, atypical presentations are observed in these populations, especially "tropical" and "ketosis-prone" atypical diabetes. Ketosis-prone atypical diabetes that has been classified by ADA as idiopathic Type 1 diabetes or Type 1b is the most common atypical form. It is characterised by an acute initial presentation with severe hyperglycaemia and ketosis, as classical Type 1 diabetes. In the subsequent clinical course after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies showed a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic B-cell autoimmunity is an exceptional finding. Association with type 1 susceptibility HLA alleles is variable. The molecular mechanisms underlining the insulin secretory dysfunction are still to be understood and may involve gluco-lipotoxicity processes, glucagon dysregulation, effect of stress, or may be genetically determined. The present review summarises the available clinical and metabolic features and suggests some pathogenetic hypotheses and principles of management for the ketosis-prone atypical diabetes of the Africans.
Africa↗
[Physical exercise and insulin sensitivity].
Physical exercise is known to be essential in the treatment of type 2 diabetes. An increased glucose uptake is evidenced during acute muscular exercise, over the post-exercise period, and following physical training. In this paper, we review metabolic and molecular aspects of physical exercise. We emphasize on the non-insulin dependent glucose transport induced by muscular contraction, which involves AMP-activated protein kinase. The discovery of this pathway is likely to open new therapeutic targets for type 2 diabetes.
Biological Transport↗
Therapeutic perspectives for type 2 diabetes mellitus: molecular and clinical insights.
Current antidiabetic agents do not suppress insulin resistance, do not reinstate physiological insulin secretion and fail to prevent the gradual loss of B-cell function. Thus, these molecules are unable to maintain long term euglycemia in all type 2 diabetic patients and there is a need for new antidiabetic drugs. Thiazolidinediones (TZD) are a new class of insulin sensitizers recently approved in Europe, in combination therapy with sulfonylureas or/and metformin, for the treatment of type 2 diabetes. TZD show beneficial effects on insulin action, glucose homeostasis and lipid metabolism despite a substantial weight gain. Their potential protective effect on B-cell function and on the development of macrovascular complication is of particular interest. Non TZD PPARgamma agonists are also under clinical trials. Other interesting therapeutic perspectives to treat insulin resistance lie in the development of inhibitors of protein tyrosine phosphatases and in the promotion of non insulin-dependent contraction-like muscle glucose uptake via stimulation of AMP protein kinase (AMPK). As to new insulin secretagogues, the phenylalanine derivative nateglinide is a first phase insulin secretion enhancer primarily intended at controlling post-prandial hyperglycemia. The most promising perspective to improve B-cell function lies in the development of glucagon-like peptide-1 (GLP-1) analogs. Clinical studies show beneficial effects on glucose homeostasis in type 2 diabetics and efficacy in sulfonylurea resistant patients without risk of hypoglycaemia. Animal studies predict beneficial effects on B-cell mass. Finally we will discuss the potential use of gene therapy to treat insulin resistance and B-cell dysfunction.
Diabetes Mellitus, Type 2↗
Diabetes in Africans. Part 1: epidemiology and clinical specificities.
The prevalence of diabetes in African communities is increasing with ageing of the population and lifestyle changes associated with rapid urbanisation and westernisation. Traditional rural communities still have very low prevalence, at most 1-2%, except in some specific high-risk groups, whereas 1-13% or more adults in urban communities have diabetes. Type 2 diabetes is the predominant form (70-90%), the rest being represented by typical type 1 patients and patients with atypical presentations that require more pathophysiological insight. Due to the high urban growth rate, dietary changes, reduction in physical activity, and increasing obesity, it is estimated that the prevalence of diabetes is due to triple within the next 25 years. In addition, long-term complications occur early in the course of diabetes and concern a high proportion of patients, probably higher than in other ethnic groups, and that could be partly explained by uncontrolled hypertension, poor metabolic control and possible ethnic predisposition. The combination of the rising prevalence of diabetes and the high rate of long-term complications in Africans will lead to a drastic increase of the burden of diabetes on health systems of African countries. The design and implementation of appropriate strategy for early diagnosis and treatment, and population-based primary prevention of diabetes in these high-risk populations is therefore a public health priority.
Africa↗
[High carcinoembryonic antigen level following cancer surgery: another way to detect thyroid medullary carcinoma].
INTRODUCTION: Thyroid medullary carcinoma is usually detected in the presence of an isolated thyroid nodule or in the context of a family disease: familial thyroid medullary carcinoma or multiple endocrine neoplasia type 2A. EXEGESIS: Here we report a third means of detection: an unexplained rise in carcinoembryonic antigen levels after cancer surgery. In each case, the carcinoembryonic antigen increase led to the assessment of the caicitonin plasma level and to a thyroid echography being performed. Thyroid medullary carcinoma was confirmed in every case after surgery. CONCLUSION: Even though the association of thyroid follicular carcinoma with familial adenomatous polyposis is common, the association of thyroid medullary carcinoma with breast or colonic carcinoma remains exceptional and probably accidental. Due to the seriousness of the thyroid medullary carcinoma, it is mandatory to look for it in the event of an unexplained rise in the carcinoembryonic antigen level, by assessing the calcitonin plasma level.
Adenocarcinoma↗
Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance.
The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors. The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in non-diabetic relatives of diabetic subjects. The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissue. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis.
Animals↗
Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha.
Phosphoinositide 3-kinases produce 3'-phosphorylated phosphoinositides that act as second messengers to recruit other signalling proteins to the membrane. Pi3ks are activated by many extracellular stimuli and have been implicated in a variety of cellular responses. The Pi3k gene family is complex and the physiological roles of different classes and isoforms are not clear. The gene Pik3r1 encodes three proteins (p85 alpha, p55 alpha and p50 alpha) that serve as regulatory subunits of class IA Pi3ks (ref. 2). Mice lacking only the p85 alpha isoform are viable but display hypoglycaemia and increased insulin sensitivity correlating with upregulation of the p55 alpha and p50 alpha variants. Here we report that loss of all protein products of Pik3r1 results in perinatal lethality. We observed, among other abnormalities, extensive hepatocyte necrosis and chylous ascites. We also noted enlarged skeletal muscle fibres, brown fat necrosis and calcification of cardiac tissue. In liver and muscle, loss of the major regulatory isoform caused a great decrease in expression and activity of class IA Pi3k catalytic subunits; nevertheless, homozygous mice still displayed hypoglycaemia, lower insulin levels and increased glucose tolerance. Our findings reveal that p55 alpha and/or p50 alpha are required for survival, but not for development of hypoglycaemia, in mice lacking p85 alpha.
Abnormalities, Multiple↗
Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85alpha regulatory subunit.
Phosphoinositide (PI) 3-kinase is a key mediator of insulin-dependent metabolic actions, including stimulation of glucose transport and glycogen synthesis. The gene for the p85alpha regulatory subunit yields three splicing variants, p85alpha, AS53/p55alpha, and p50alpha. All three have (i) a C-terminal structure consisting of two Src homology 2 domains flanking the p110 catalytic subunit-binding domain and (ii) a unique N-terminal region of 304, 34, and 6 amino acids, respectively. To determine if these regulatory subunits differ in their effects on enzyme activity and signal transduction from insulin receptor substrate (IRS) proteins under physiological conditions, we expressed each regulatory subunit in fully differentiated L6 myotubes using adenovirus-mediated gene transfer with or without coexpression of the p110alpha catalytic subunit. PI 3-kinase activity associated with p50alpha was greater than that associated with p85alpha or AS53. Increasing the level of p85alpha or AS53, but not p50alpha, inhibited both phosphotyrosine-associated and p110-associated PI 3-kinase activities. Expression of a p85alpha mutant lacking the p110-binding site (Deltap85) also inhibited phosphotyrosine-associated PI 3-kinase activity but not p110-associated activity. Insulin stimulation of two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase (p70(S6K)), was decreased in cells expressing p85alpha or AS53 but not in cells expressing p50alpha. Similar inhibition of PI 3-kinase, Akt, and p70(S6K) was observed, even when p110alpha was coexpressed with p85alpha or AS53. Expression of p110alpha alone dramatically increased glucose transport but decreased glycogen synthase activity. This effect was reduced when p110alpha was coexpressed with any of the three regulatory subunits. Thus, the three different isoforms of regulatory subunit can relay the signal from IRS proteins to the p110 catalytic subunit with different efficiencies. They also negatively modulate the PI 3-kinase catalytic activity but to different extents, dependent on the unique N-terminal structure of each isoform. These data also suggest the existence of a mechanism by which regulatory subunits modulate the PI 3-kinase-mediated signals, independent of the kinase activity, possibly through subcellular localization of the catalytic subunit or interaction with additional signaling molecules.
Adenoviridae↗
Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle.
Obesity and insulin resistance in skeletal muscle are two major factors in the pathogenesis of type 2 diabetes. Mice with muscle-specific inactivation of the insulin receptor gene (MIRKO) are normoglycemic but have increased fat mass. To identify the potential mechanism for this important association, we examined insulin action in specific tissues of MIRKO and control mice under hyperinsulinemic-euglycemic conditions. We found that insulin-stimulated muscle glucose transport and glycogen synthesis were decreased by about 80% in MIRKO mice, whereas insulin-stimulated fat glucose transport was increased threefold in MIRKO mice. These data demonstrate that selective insulin resistance in muscle promotes redistribution of substrates to adipose tissue thereby contributing to increased adiposity and development of the prediabetic syndrome.
Adipose Tissue↗
A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes.
Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.
Acute-Phase Reaction↗
Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: what can we learn from transgenic and knockout mice?
The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic B-cells to compensate by adequate insulin secretion. Here, we review studies obtained from genetically engineered mice that have helped dissect the pathophysiology of this disease. Transgenic/knockout models with monogenic impairment in insulin action and insulin secretion have highlighted potential molecular mechanisms for insulin resistance and suggested a mechanism for the development of MODY in humans. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, pointing out the importance of interactions of different genetic loci in the production of diabetes. Tissue-specific knockouts of the insulin receptor have challenged current concepts on the regulation of glucose homeostasis and have highlighted the importance of insulin action in pancreatic B-cells and brain. The impact of the genetic background on insulin action, insulin secretion and the incidence of diabetes is also evident in these models. These findings highlight potential new therapeutic targets in the treatment of type 2 diabetes.
Animals↗
Identification of the rat adapter Grb14 as an inhibitor of insulin actions.
We cloned by interaction with the beta-subunit of the insulin receptor the rat variant of the human adapter Grb14 (rGrb14). rGrb14 is specifically expressed in rat insulin-sensitive tissues and in the brain. The binding of rGrb14 to insulin receptors is insulin-dependent in vivo in Chinese hamster ovary (CHO) cells overexpressing both proteins and importantly, in rat liver expressing physiological levels of proteins. However, rGrb14 is not a substrate of the tyrosine kinase of the receptor. In the two-hybrid system, two domains of rGrb14 can mediate the interaction with insulin receptors: the Src homology 2 (SH2) domain and a region between the PH and SH2 domains that we named PIR (for phosphorylated insulin receptor-interacting region). In vitro interaction assays using deletion mutants of rGrb14 show that the PIR, but not the SH2 domain, is able to coprecipitate insulin receptors, suggesting that the PIR is the major binding domain of rGrb14. The interaction between rGrb14 and the insulin receptors is almost abolished by mutating tyrosine residue Tyr1150 or Tyr1151 of the receptor. The overexpression of rGrb14 in CHO-IR cells decreases insulin stimulation of both DNA and glycogen synthesis. These effects are accompanied by a decrease in insulin-stimulated tyrosine phosphorylation of IRS-1, but insulin receptor autophosphorylation is unaltered. These findings suggest that rGrb14 could be a new downstream signaling component of the insulin-mediated pathways.
Adaptor Proteins, Signal Transducing↗
A novel recognition site for somatostatin-14 on the GABA(A) receptor complex.
Functional interactions between gamma-aminobutyric acid (GABA) and somatostatin are suggested by the presence of synaptic contacts between GABA and somatostatin neurons, colocalisation of GABA and somatostatin and reciprocal modulation of somatostatin and GABA release. Nevertheless, a direct interaction of somatostatin with the GABA(A) receptor complex has not yet been investigated. A quantitative autoradiographic technique was used to determine the ability of somatostatin to interact with the [35S]t-butylbicyclophosphothionate [35S]TBPS binding sites of the GABA(A) receptor complex: somatostatin inhibited [35S]TBPS binding with IC50 values in the micromolar range in all brain regions studied. These results demonstrate for the first time a direct interaction between somatostatin and the GABA(A) receptor complex.
Animals↗