1/78. Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation.We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in situ activation of the receptor kinase in skeletal muscle was reduced about 70%. Selection of only those receptors that bound to anti-phosphotyrosine antibody showed that these receptors had normal kinase activity and that the reduction in overall kinase activity was due to the inability of about 70% of the receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother's skeletal muscle, suggesting that virtually no truncated receptor was expressed. Receptor kinase activity was, however, reduced by 95 and 91% in the compound heterozygous brothers. This suggests that the mother's mutated allele contributes little to the generation of functional receptor protein and that the receptors in the mother's skeletal muscle are transcribed almost exclusively from the non-mutated allele. The mutation in exon 17 could lead to reduced transcription or rapid degradation of a predominantly transcribed truncated gene product or both.- - - - - - - - - - ranking = 1keywords = fat (Clic here for more details about this article) |
2/78. Triglyceride-induced diabetes associated with familial lipoprotein lipase deficiency.Raised plasma triglycerides (TGs) and nonesterified fatty acid (NEFA) concentrations are thought to play a role in the pathogenesis of insulin-resistant diabetes. We report on two sisters with extreme hypertriglyceridemia and overt diabetes, in whom surgical normalization of TGs cured the diabetes. In all of the family members (parents, two affected sisters, ages 18 and 15 years, and an 11-year-old unaffected sister), we measured oral glucose tolerance, insulin sensitivity (by the euglycemic-hyperinsulinemic clamp technique), substrate oxidation (indirect calorimetry), endogenous glucose production (by the [6,6-2H2]glucose technique), and postheparin plasma lipoprotein lipase (LPL) activity. In addition, GC-clamped polymerase chain reaction-amplified dna from the promoter region and the 10 coding LPL gene exons were screened for nucleotide substitution. Two silent mutations were found in the father's exon 4 (Glu118 Glu) and in the mother's exon 8 (Thr361 Thr), while a nonsense mutation (Ser447 Ter) was detected in the mother's exon 9. Mutations in exons 4 and 8 were inherited by the two affected girls. At 1-2 years after the appearance of hyperchylomicronemia, both sisters developed hyperglycemia with severe insulin resistance. Because medical therapy (including high-dose insulin) failed to reduce plasma TGs or control glycemia, lipid malabsorption was surgically induced by a modified biliopancreatic diversion. Within 3 weeks of surgery, plasma TGs and NEFA and cholesterol levels were drastically lowered. Concurrently, fasting plasma glucose levels fell from 17 to 5 mmol/l (with no therapy), while insulin-stimulated glucose uptake, oxidation, and storage were all markedly improved. Throughout the observation period, plasma TG levels were closely correlated with both plasma glucose and insulin concentrations, as measured during the oral glucose tolerance test. These cases provide evidence that insulin-resistant diabetes can be caused by extremely high levels of TGs.- - - - - - - - - - ranking = 2keywords = fat (Clic here for more details about this article) |
3/78. Antiinsulin receptor autoantibodies induce insulin receptors to constitutively associate with insulin receptor substrate-1 and -2 and cause severe cell resistance to both insulin and insulin-like growth factor i.We report here that antiinsulin receptor (anti-IR) autoantibodies (AIRs) from a newly diagnosed patient with type B syndrome of insulin resistance induced cellular resistance not only to insulin but also to insulin-like growth factor i (IGF-I) for the stimulation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase activities and of glycogen and dna syntheses. The molecular mechanisms of this dual resistance were investigated. Patient AIRs bound the IR at the insulin-binding site and caused insulin resistance at the IR level by inducing a 50% decrease in cell surface IRs and a severe defect in the tyrosine kinase activity of the residual IRs, manifested by a loss of insulin-stimulated IR autophosphorylation and IR substrate-1 (IRS-1)/IRS-2 phosphorylation. In contrast, cell resistance to IGF-I occurred at a step distal to IGF-I receptors (IGF-IRs), as AIRs altered neither IGF-I binding nor IGF-I-induced IGF-IR autophosphorylation, but inhibited the ability of IGF-IRs to mediate tyrosine phosphorylation of IRS-1 and IRS-2 in response to IGF-I. Coimmunoprecipitation assays showed that in air-treated cells, IRs, but not IGF-IRs, were constitutively associated with IRS-1 and IRS-2, strongly suggesting that air-desensitized IRs impeded IGF-I action by sequestering IRS-1 and IRS-2. Accordingly, AIRs had no effect on the stimulation of mitogen-activated protein kinase activity or dna synthesis by vanadyl sulfate, FCS, epidermal growth factor, or platelet-derived growth factor, all of which activate signaling pathways independent of IRS-1/IRS-2. Thus, AIRs induced cell resistance to both insulin and IGF-I through a novel mechanism involving a constitutive and stable association of IRS-1 and IRS-2 with the IR.- - - - - - - - - - ranking = 1keywords = fat (Clic here for more details about this article) |
4/78. A gene for congenital generalized lipodystrophy maps to human chromosome 9q34.Congenital generalized lipodystrophy (CGL, Berardinelli-Seip syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid x receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.- - - - - - - - - - ranking = 88.197391789176keywords = adipose (Clic here for more details about this article) |
5/78. Effects of insulin-like growth factor i (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion.We have recently reported a patient with a homozygous partial deletion of the insulin-like growth factor-I (IGF-I) gene, resulting in IGF-I deficiency, insulin resistance, and short stature. Recombinant human IGF-I (rhIGF-I) therapy has been shown to improve insulin sensitivity (Si) and growth in other causes of IGF-I deficiency. We now report results of 1 yr of rhIGF-I therapy on body composition, bone mineral density (BMD), insulin sensitivity, and linear growth in this patient. rhIGF-I therapy was initiated at age 16.07 yr (bone age, 14.2 yr), at a starting dose of 40 microg/kg daily, increasing after 3 months to 80 microg/kg daily. body composition, BMD, markers of bone mineralization, and auxological parameters (height, weight) were measured at 0, 6, and 12 months after start of therapy. Si, acute insulin response to glucose, and glucose effectiveness were determined at baseline, 3 months, and 12 months into therapy. On IGF-I therapy, body mass index increased from 17 kg/m2 to 18.6 kg/m2. body composition studies (dual-energy x-ray absorbtiometry) revealed an initial decrease in total body fat, from 19.9% at baseline to 15.1% at 6 months; but by 12 months of therapy, this had reversed, with an increase to 21.8%. Si, calculated using Bergman's minimal model, was substantially reduced at baseline at 1.45 x 10-4 min-1 (microU/mL) [normal value, 5.1 x 10-4 min 1 (lean adult male)]. rhIGF-I therapy resulted in a dose-related improvement of Si into the normal range (NR) (rhIGF-I dose: 40 microg/kg x day, Si = 2.06 x 10-4 min-l; rhIGF-I dose: 80 microg/kg x day, Si = 4.39 x 10-4 min-1). Baseline reduction in Si was accompanied by elevated acute insulin response to glucose, which also fell in a dose-dependent manner. Baseline BMD was severely reduced when compared with age-matched controls (-4.88 SD); however, calculation of bone mineral apparent density indicated that the true reduction in BMD was minimal. rhIGF-I therapy increased BMD by 17% and bone mineral apparent density by 7%, indicating that IGF-I has a greater effect on bone growth than bone mineralization. Bone turnover markers also increased on rhIGF-I; mean serum osteocalcin: 8.3 ng/mL pretreatment, 21.7 ng/mL after 6 months of rhIGF-I (NR for adult male, 3.4-9.1 ng/mL); mean bone specific alkaline phosphatase: 36.5 U/L pretreatment, 82.2 U/L after 6 months of therapy (NR for adult male, 15-41). Height velocity increased from 3.8 cm/yr pretreatment to 7.3 cm/yr on 80 microg/kg.day of rhIGF-I. In this patient with severe insulin resistance, therapy with rhIGF-I resulted in beneficial effects on Si, body composition, bone size, and linear growth. These results have implications for IGF-I therapy in a variety insulin resistant states.- - - - - - - - - - ranking = 1keywords = fat (Clic here for more details about this article) |
6/78. insulin resistance caused by massive degradation of subcutaneous insulin.Severe resistance to subcutaneous insulin but sensitivity to intravenous insulin persisted for 15 months in a 17-year-old diabetic girl. Heat-labile insulin-degrading activity was present in the patient's ketotic sera and in the 100,000 g fraction (soluble fraction) of adipose tissue. serum-degrading activity was not inhibited by N-ethylmaleimide. The soluble fraction also degraded glucagon and B chain but not growth hormone or myoglobin. It was inhibited by incubation with the patient's nonketotic sera, normal sera, or Trasylol. glutathione-insulin-transhydrogenase (GIT) activity was 66% of normal. The biopsy of adipose tissue at remission showed a normal level of insulin- and glucagon-degrading activity. The activity was eluted from Sephadex G200 as a single peak and had properties consistent with those of the insulin-specific protease (ISP). The increased degrading activity present during insulin resistance had properties not shared with ISP, suggesting the presence of an uncharacterized protease.- - - - - - - - - - ranking = 88.197391789176keywords = adipose (Clic here for more details about this article) |
7/78. Cardiac involvement in total generalized lipodystrophy (Berardinelli- Seip syndrome).Total generalized lipodystrophy (Berardinelli - Seip syndrome) is a rare hereditary disease characterized by insulin-resistant diabetes mellitus and a small quantity of adipose tissue and is of unknown origin. Common cardiovascular alterations related to this syndrome are cardiac hypertrophy and arterial hypertension. This article reports a case of Berardinelli - Seip syndrome and reviews the literature with special emphasis on the cardiovascular manifestations of this syndrome.- - - - - - - - - - ranking = 44.098695894588keywords = adipose (Clic here for more details about this article) |
8/78. Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation.BACKGROUND: Lipoatrophic diabetes is an insulin resistance syndrome characterized by the complete or partial lack of adipose tissue and disturbances in lipid and glucose metabolism. Nonalcoholic steatohepatitis (NASH) is a well-described change in liver pathology consisting of steatosis, hepatitis, and fibrosis that can be associated with lipoatrophic diabetes. RESULTS: This article describes the first reported case of lipoatrophic diabetes with NASH leading to liver failure and liver transplantation. Before transplantation, the patient required 600-700 U of insulin/day. After transplantation, a dramatic decline in her insulin requirements was observed, despite corticosteroids. Eighteen months after transplantation, her glycemic control worsened, and she developed recurrent NASH on serial liver biopsies. CONCLUSIONS: NASH associated with lipoatrophic diabetes can recur after liver transplantation, and in this case, was accompanied by increased insulin requirements. These results suggest that the development of NASH itself may contribute to the insulin resistance observed in lipoatrophic diabetes.- - - - - - - - - - ranking = 44.098695894588keywords = adipose (Clic here for more details about this article) |
9/78. Enhanced intra-abdominal visceral fat accumulation in patients with Werner's syndrome.OBJECTIVE: Studies were made on the abnormality of glucose and lipid metabolism and its cause in four patients with Werner's syndrome to infer the reason for accelerated atherogenesis in this syndrome. RESULTS: Of these four patients, hypercholesterolemia was found in three, hypertriglyceridemia in four, hypoalphalipoproteinemia in two and hypertension in two. All the patients had insulin-resistant diabetes mellitus and three of them had apparent hyperinsulinemia. Abdominal computed tomography revealed that all of them had visceral fat obesity, namely augumented intra-abdominal adipose tissue. CONCLUSION: The clinical features of these patients resemble those recently designated as insulin resistant syndrome (syndrome X) or visceral fat syndrome. The metabolic abnormality may be one of important factors in the accelerated atherogenesis in this syndrome.- - - - - - - - - - ranking = 50.098695894588keywords = adipose, fat (Clic here for more details about this article) |
10/78. syndrome of lipodystrophy, hyperlipidemia, insulin resistance, and diabetes in treated patients with human immunodeficiency virus infection.OBJECTIVE: To describe the syndrome of lipodystrophy, hyperlipidemia, insulin resistance, and diabetes in patients with human immunodeficiency virus (hiv) infection treated with protease inhibitor drugs. methods: This is a case series of patients referred from an infectious disease clinic to a diabetes-endocrinology clinic in an academic medical center because of severe metabolic problems that occurred during the course of otherwise-successful treatment of hiv infection. The clinical course, abnormalities on physical examination, laboratory data, and complications are described and analyzed. The pathogenesis of the syndrome is discussed and compared with that of type 2 diabetes, lipoatrophic diabetes, and mouse models of lipodystrophy. RESULTS: In six male patients receiving antiretroviral therapy for hiv infection, a syndrome of lipoatrophy of the face, legs, and buttocks, hyperlipidemia (predominantly hypertriglyceridemia), and type 2 diabetes mellitus was noted. Two patients had pronounced abdominal obesity, in contrast to their thin extremities. Five of the six patients were receiving protease inhibitor drugs, which have been thought to contribute to metabolic abnormalities. In two patients, ischemic heart disease had developed. CONCLUSION: protease inhibitors frequently cause insulin resistance and lipoatrophy in subcutaneous adipose tissue. These abnormalities are associated with visceral adiposity, hyperlipidemia, diabetes, and cardiovascular consequences and represent an important and unsolved problem in the treatment of hiv-infected patients.- - - - - - - - - - ranking = 44.098695894588keywords = adipose (Clic here for more details about this article) |
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