1/4. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature.We present clinical descriptions, metabolic features, and patterns of body fat loss of 16 patients with acquired generalized lipodystrophy (AGL) seen by us over the last 10 years. In addition, we review 63 cases of AGL reported in the literature. Based on these data, we propose new diagnostic criteria for AGL, the essential criterion being selective loss of body fat from large regions of the body occurring after birth. We also propose a subclassification of AGL into 3 varieties, type 1, the panniculitis variety; type 2, the autoimmune disease variety; and type 3, the idiopathic variety, which affect nearly 25%, 25%, and 50% of patients, respectively. Most of the patients presented in childhood and adolescence. Females were affected approximately 3 times more than males. subcutaneous fat loss was severe and usually affected the face, trunk, abdomen, and extremities. In some patients, fat loss also involved the palms and soles and intraabdominal region; however, the bone marrow and retroorbital fat were preserved in all patients. Clinically, patients may have voracious appetite, fatigue, and acanthosis nigricans. hepatomegaly was common, mostly due to hepatic steatosis. Most AGL patients had fasting and/or postprandial hyperinsulinemia, diabetes mellitus, hypertriglyceridemia, and low serum levels of high-density lipoprotein cholesterol, leptin, and adiponectin. diabetes mellitus and hypertriglyceridemia were less prevalent in the panniculitis variety compared with the idiopathic and autoimmune varieties. The management of AGL includes cosmetic surgery for loss of fat. Severe hypertriglyceridemia should be treated with a very low-fat diet and omega-3 polyunsaturated fatty acid supplementation from fish oils. Management of diabetes is difficult and may necessitate insulin therapy in large doses. Insulin sensitizers such as metformin and thiazolidinediones have been used, although their long-term efficacy and safety remain unknown. Subcutaneous administration of recombinant leptin in AGL patients with hypoleptinemia effectively improves hyperglycemia, hypertriglyceridemia, and hepatic steatosis. leptin therapy, however, remains investigational. Fibrates alone or in combination with statins may be used to treat hypertriglyceridemia.- - - - - - - - - - ranking = 1keywords = hyperinsulinemia (Clic here for more details about this article) |
2/4. A nonsense mutation in the Arg345 of the insulin receptor gene in a Japanese type A insulin-resistant patient.Defects in insulin receptor function have been associated with insulin resistant states such as obesity and type 2 diabetes mellitus. Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of extreme insulin resistance. We have studied a 10-year-old Japanese girl with type A insulin resistance with hirsutism and hyperinsulinemia but without the dysmorphic features characteristic of leprechaunism or Rabson-Mendenhall syndrome. Despite the presence of severe insulin resistance, the patient did not develop overt diabetes mellitus at the time of investigation. Using direct sequencing, we identified a nonsense mutation causing premature termination after amino acid 345 in the alpha subunit of the insulin receptor.- - - - - - - - - - ranking = 1keywords = hyperinsulinemia (Clic here for more details about this article) |
3/4. Familial hyperproinsulinemia associated with NIDDM. A case study.OBJECTIVE--To report studies on an elderly patient with moderate NIDDM associated with marked fasting hyperinsulinemia. research design AND methods--The propositus and several family members were studied by a combination of clinical, biochemical, and molecular genetic approaches to define the underlying genetic defect. RESULTS--fasting levels of contrainsulin hormones were normal, and resistance to exogenous insulin was absent. Gel filtration and reverse-phase high-performance liquid chromatography revealed elevated amounts of a structurally abnormal proinsulin intermediate (AC proinsulin). A study of the family of the propositus showed the same abnormality in 4 of 5 members in 3 successive generations. Genetic analysis revealed a point mutation affecting residue 65 of human proinsulin (Arg-->His) in one allele of the insulin gene in the propositus, a defect similar to that described previously in 3 other apparently unrelated lineages. CONCLUSIONS--This family exhibits a clear-cut relationship between increasing age and metabolic decompensation in all the hyperproinsulinemic members, suggesting that (inherited) metabolic stress and age both contribute to development of diabetes mellitus.- - - - - - - - - - ranking = 1keywords = hyperinsulinemia (Clic here for more details about this article) |
4/4. Hyperproinsulinemia in a three-generation Caucasian family due to mutant proinsulin (Arg65-His) not associated with imparied glucose tolerance: the contribution of mutant proinsulin to insulin bioactivity.Familial hyperproinsulinemia is a genetic abnormality characterized by an increased proportion of proinsulin immunoreactivity in the circulation due to mutations affecting the posttranslational processing of proinsulin. In affected Japanese families, this has been associated with noninsulin-dependent diabetes mellitus or impaired glucose tolerance. A three-generation Caucasian family with hyperproinsulinemia was identified through unexplained hyperinsulinemia in a normal volunteer participating in a metabolic study. High pressure liquid chromatography analysis of fasting plasma revealed a major peak eluting close to the position of proinsulin. Direct sequencing of the proinsulin gene exon 3 showed a heterozygous point mutation (CGT-->CAT) resulting in the substitution of Arg-->His in position 65 (corresponding to the AC cleavage site) in the index case, his mother, and his maternal grandmother. Using specific enzyme-linked immunosorbent assay methods to quantify insulin and proinsulin (including its conversion intermediates), the impact of this mutation on B cell secretion and glucose tolerance was studied. All affected subjects had normal oral glucose tolerance. In the basal state and after oral glucose administration, their proinsulin responses were immense, but intact insulin responses were slightly reduced. However, when calculating insulin bioactivity by assuming 9% activity for mutant Arg65-->His proinsulin, responses in affected subjects were comparable to those in normal subjects. In conclusion, our data demonstrate hyperproinsulinemia in a three-generation Caucasian family due to heterozygous mutant Arg65-->His proinsulin. This was not associated with impaired glucose tolerance. These results suggest that this mutation in the heterozygous state per se does not affect glucose tolerance and that the biological activity of mutant proinsulin contributes to glucose homeostasis in this family. The association of the same mutation with impaired glucose tolerance or diabetes in previous studies may be the result of selection bias or associated conditions (e.g. the genetic background of the kindreds examined).- - - - - - - - - - ranking = 1keywords = hyperinsulinemia (Clic here for more details about this article) |