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PubMed2004

The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells.

Defects in insulin secretion, resulting from loss of function or destruction of pancreatic beta-cells, trigger diabetes. Interleukin (IL)-1beta is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs beta-cell survival and function. Because effective insulin signaling is required for the optimal beta-cell function, we assessed the effect of IL-1beta on the insulin pathway in a rat pancreatic beta-cell line. We show that IL-1beta decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1beta-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1beta inhibitory effect on insulin signaling in these cells. We show that IL-1beta increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1beta treatment in RINm5F cells. We propose that IL-1beta decreases insulin action in beta-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced beta-cell survival.

Animals↗
PubMed1990

Lessons learned from molecular biology of insulin-gene mutations.

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate beta-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibits markedly altered subcellular sorting behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

HLA-DQ associations distinguish insulin-resistant and insulin-sensitive variants of NIDDM in black Americans.

OBJECTIVE: NIDDM in black Americans exists as two variants: one with a primary defect in insulin action (insulin-resistant variant) and the other with normal insulin action and a primary defect in insulin secretion (insulin-sensitive variant). The objective of this study was to determine whether these two variants were genetically distinct from each other and from normal control subjects as determined by HLA typing. RESEARCH DESIGN AND METHODS: Insulin action was measured with the euglycemic insulin clamp with a 1 mU.kg-1.min-1 insulin infusion with [3-3H]glucose. A glucose disposal of < 278 mumol.kg-1.min-1 was considered insulin resistant, and a value greater than this was considered insulin sensitive. The study population consisted of 21 insulin-resistant and 25 insulin-sensitive black NIDDM patients and 89 normal, nondiabetic black control subjects from an urban hospital. HLA typing was performed with serological methods. RESULTS: The frequency of HLA-DQW7 in the insulin-resistant population (76%) was significantly greater than that in the insulin-sensitive population (32%, corrected P < 0.018) and the normal control population (21%, corrected P < 0.001). The frequency of HLA-DQW6 was increased in the insulin-sensitive population (76%), corrected P < 0.023, as compared with the normal control subjects (33%). The relative risk of HLA-DQW7 in identifying insulin-resistant NIDDM patients compared with control subjects was 7. CONCLUSIONS: At least one component that differentiates insulin-resistant and insulin-sensitive NIDDM in black Americans is under different genetic control. One or more loci responsible for insulin-resistant and insulin-sensitive NIDDM are likely to be in linkage disequilibrium with the DQ locus of the human MHC region of chromosome 6.

Alleles↗
PubMed2004

Insulin resistance, impaired early insulin response, and insulin propeptides as predictors of the development of type 2 diabetes: a population-based, 7-year follow-up study in 70-year-old men.

OBJECTIVE: Defects in insulin secretion and insulin action are the major abnormalities in the development of type 2 diabetes. In middle-aged subjects, elevated plasma proinsulin has been found to predict type 2 diabetes. Therefore, our aim was to study the longitudinal relationships between baseline determinations of insulin sensitivity index (S(i)) assessed by euglycemic insulin clamp, the early insulin response (EIR) at an oral glucose tolerance test (OGTT), fasting intact proinsulin, 32-33 split proinsulin and specific insulin, and the development of type 2 diabetes in a population-based cohort of 70-year-old nondiabetic men (n = 667) with 7-year follow-up. RESEARCH DESIGN AND METHODS: A euglycemic insulin clamp study and a 75-g OGTT were performed at baseline, and fasting peptide concentrations were measured using specific two-site immunometric assays. Results from logistic regression models are presented as odds ratios (ORs) with 95% CIs for a 1-SD increase in the predictor variable. RESULTS: In separate multivariate analyses adjusted for EIR (OR 0.72, 95% CI 0.59-0.89) and S(i) (0.68, 0.58-0.88), 32-33 split proinsulin (1.49, 1.18-1.88) or intact proinsulin (1.30, 1.04-1.63) were significantly associated with the development of type 2 diabetes, whereas specific insulin (1.24, 0.91-1.66) was not. The significant associations between 32-33 split or intact proinsulin and the development of type 2 diabetes were unaltered after adjustment for BMI and glucose tolerance. CONCLUSIONS: Insulin propeptides predicted type 2 diabetes over a 7-year period in elderly men, independent of the EIR and S(i).

Aged↗
PubMed2004

Does the aspartic acid to asparagine substitution at position 76 in the pancreas duodenum homeobox gene (PDX1) cause late-onset type 2 diabetes?

OBJECTIVE: Considerable data support an inherited defect in insulin secretion as one component of type 2 diabetes. Coding variants of the pancreas duodenum homeobox gene (PDX1) were proposed to predispose late-onset type 2 diabetes and to decrease transactivation in vitro. We tested the hypothesis that the Asp76Asn (D76N) variant that was identified in several populations predisposed type 2 diabetes and reduced insulin secretion. RESEARCH DESIGN AND METHODS: We performed a case-control study in 191 control subjects and 190 individuals with type 2 diabetes, all of European descent, then characterized the D76N variant in 704 members of 68 families. We compared the phenotypic characteristics of those with and without the variant by diagnostic status and determined the insulin secretory response to intravenous glucose and tolbutamide among nondiabetic family members. RESULTS: D76N was not associated with type 2 diabetes, either in our population or when all reported studies in Caucasians were combined. D76N did not segregate with diabetes among the families examined. Among D76N carriers, nondiabetic individuals had a lower waist-to-hip ratio and a trend to lower BMI than their diabetic counterparts. Diabetic carriers of D76N were significantly leaner by BMI (P = 0.012) and tended to be younger than diabetic individuals with the D/D genotype. However, insulin secretion in response to oral and intravenous glucose challenge and to intravenous tolbutamide was not reduced in D76N carriers. CONCLUSIONS: The D76N variant of PDX1 does not significantly alter insulin secretion or act as a high-risk susceptibility allele for late-onset type 2 diabetes as proposed previously, although we cannot exclude a minor role in increasing risk of diabetes.

Age of Onset↗
PubMed1984

IgA deficiency during aurothioglucose treatment. A case report.

A 43-year-old woman with seronegative rheumatoid arthritis developed a selective IgA deficiency during aurothioglucose treatment. No antibodies against IgA were detectable in the serum; normal numbers of IgA, IgG and IgM positive cells were demonstrated by immunofluorescence studies on a biopsy specimen from the small intestine. These data would suggest a defect in IgA secretion rather than in production by plasma cells.

Adult↗
PubMed2000

Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy.

The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) can be related to abnormalities in the metabolism and disposition of sex hormones and/or bile acids, determined by a genetic predisposition interacting with environmental factors. The total amount of oestrogens and progesterone circulating in the blood or excreted in the urine of ICP patients is similar to normal pregnancies. Thus, the search for the cause has been focused on abnormal hormone metabolites. The cholestatic potential of some D-ring oestrogen metabolites is supported by experimental and clinical data. Similar observations with regard to bile acids and progesterone metabolites are still scarce. This article reviews current knowledge in this field, including our own data. Bile acid synthesis appears to be reduced in patients with ICP, in whom primary conjugated bile acids are retained in blood. The major bile acid in blood and urine of these patients is cholic acid instead of chenodeoxycholic acid present in normal pregnancies. Hydroxylation and sulfation of bile acids are enhanced, while glucuronidation appears to be of lesser importance. The synthesis of progesterone appears unimpaired, while the profiles of progesterone metabolites in plasma and urine are different from normal pregnancies, with a larger proportion of mono- and disulfated metabolites, mainly 3alpha,5alpha isomers. Glucuronidated metabolites, however, are unchanged. With the administration of ursodeoxycholic acid (UDCA) to patients with ICP, pruritus and serum liver values are improved, the concentration of bile acids in blood is diminished and the proportion of their conjugated metabolites returned to normal. Simultaneously, the concentration of sulfated progesterone metabolites in blood and their urinary excretion are reduced. The serum levels of bile acids and progesterone metabolites before UDCA administration and their decrease during treatment do not correlate with each other. We propose that patients with ICP have a selective defect in the secretion of sulfated progesterone metabolites into bile and speculate that this may be caused by genetic polymorphism of canalicular transporter(s) for steroid sulfates or their regulation. Interaction with oestrogen metabolites and/or some exogenous compounds may further enhance the process triggering ICP in genetically predisposed individuals.

Bile Acids and Salts↗
PubMed1991

Enzymes and factors controlling vitamin D metabolism and action in normal and milk fever cows.

In milk fever (parturient paresis), calcium homeostatic mechanisms, regulated by parathyroid hormone and 1,25-dihydroxyvitamin D, fail to maintain normal blood calcium concentrations, resulting in severe hypocalcemia. The precise nature of the endocrine defect is unknown. Secretion of parathyroid hormone and production of 1,25-dihydroxyvitamin D is similar in most cows with milk fever or without. However, there are some cows that fail to produce adequate 1,25-dihydroxyvitamin D at the onset of lactation. These tend to be cows that will suffer prolonged hypocalcemia and relapse after treatment. Assuming that most cows produce adequate amounts of both hormones, the next logical cause of milk fever might be a failure of tissues to respond to calcium-regulating hormones. Older cows are more likely to develop milk fever than younger ones. We have found that tissue 1,25-dihydroxyvitamin D receptor concentrations decline with age, leaving the tissues less able to respond to 1,25-dihydroxyvitamin D. We also have found that tissue 1,25-dihydroxyvitamin D receptor concentrations increase during pregnancy and lactation in the cow. Intestinal 1,25-dihydroxyvitamin D receptor concentration does not appear to be different in cows with or without milk fever in cows of similar ages. However, intestinal 1,25-dihydroxyvitamin D receptor numbers decrease precipitously at parturition, which may in part be responsible for the development of hypocalcemia in dairy cattle.

Absorption↗
PubMed1989

A diabetic-like condition of turkey embryos maintained in shell-less culture.

Serum insulin concentration and pancreatic insulin content were determined for turkey embryos incubated in ovo and in long-term shell-less culture (ex ovo). Insulin was undetectable (less than 10 pg) in serum from 87% of the ex ovo embryos compared with their in ovo counterparts. This was evident at all incubation ages, although insulin was detectable in more of the ex ovo embryos on Day 24. Insulin increased in the embryos incubated in ovo from 122 (Day 15) to levels exceeding 2000 pg/ml at hatching. Total pancreatic insulin content was greater in the cultured embryos on Days 15, 17, and 22 compared with their in ovo counterparts. Serum glucose was significantly greater (P less than 0.05) in the ex ovo embryos at all ages. In response to an infusion of L-arginine, serum insulin increased from 566 to 1256 pg/ml in the in ovo embryos, whereas no change was evident in the ex ovo embryos (233 vs 257 pg/ml). When embryos incubated in ovo were injected with insulin, a significant (P less than 0.05) reduction of serum glucose was observed at 60 min after injection. Serum glucose concentrations remained elevated in the embryos incubated ex ovo despite the insulin injection. Liver glucose 6-phosphatase activity, assessed on Days 15 and 22 of incubation, was found to be significantly (P less than 0.05) lower in the ex ovo embryos. Turkey embryos incubated in shell-less culture exhibited chronic hyperglycemia in concert with extremely low circulating levels of insulin. The pancreatic beta cells of these embryos were not responsive to arginine or elevated glucose. Taken together these findings suggest the occurrence of a diabetic-like condition in the ex ovo embryos. This defect in insulin secretion may, in part, be responsible for some of the developmental abnormalities characteristic of the turkey embryo cultured ex ovo.

Animals↗
PubMed2000

[Relative importance of insulin actin in insulin's target tissues].

Insulin is a hormone with various metabolic effects such as glucose uptake and glycogen synthesis in insulin's target tissues. Skeletal muscle has been considered to be a principal site of insulin resistance in type 2 diabetes. Studies of mice with muscle specific-knockout of the insulin receptor demonstrated that although skeletal muscle was insulin resistant, glucose tolerance was near normal at the whole body, indicating the possible importance of liver. beta cell specific disruption of the insulin receptor indicated that primary insulin resistance at the beta cells resulted in a defect of insulin secretion and impaired glucose tolerance. These animal models suggest that a combination of insulin resistance in muscle, liver, adipose cells, and beta cells appears to create the phenotype of type 2 diabetes.

Adipocytes↗
PubMed2000

Type 2 diabetes worldwide according to the new classification and criteria.

Two major reports have recently revised the classification of and diagnostic criteria for diabetes. Classification was previously based on the need for insulin (insulin-dependent or non-insulin-dependent), but this has become increasingly confusing. Now, the type of diabetes is determined by the etiological process rather than the treatment modality. Type 1 diabetes is thus characterized by islet cell destruction and type 2 diabetes by a combination of defects in insulin secretion and action. An individual with either type of diabetes may be on any treatment modality. This classification should prove to be more logical and, for example, allow latent autoimmune diabetes in adults, which typically does not require insulin at presentation, to be classified as type 1 diabetes. The fasting plasma glucose diagnostic threshold for diabetes has been lowered to 7.0 mmol/l (126 mg/dl), and impaired fasting glucose (fasting plasma glucose 6.1-6.9 mmol/l [110-125 mg/dl]) has been introduced as a new category of intermediate glucose metabolism. These changes recognize that the old fasting threshold did not match the 2-h (postload) threshold well and that both micro- and macrovascular disease develop at lower fasting glucose levels than previously recognized. Although the prevalences of diabetes according to the new fasting and 2-h criteria are now similar in most populations, the actual individuals identified as having diabetes are often different. Over 30% of all those with diabetes have a nondiabetic fasting glucose but still have increased cardiovascular mortality. Thus, it is important to retain the oral glucose tolerance test for the diagnosis of diabetes.

Blood Glucose↗
PubMed2000

Homozygous truncation of the fibrinogen A alpha chain within the coiled coil causes congenital afibrinogenemia.

The molecular basis of a novel congenital afibrinogenemia has been determined. The proposita, the only affected member in a consanguineous Norwegian family, suffers from a moderate to severe bleeding disorder due to the total absence of any detectable fibrinogen. Dot blots of solubilized platelets revealed a small amount of gamma chain but no A alpha or B beta chains, whereas no chains were detected in plasma dot blots. DNA sequencing of the A alpha chain gene revealed a homozygous C-->T transversion 557 nucleotides from the transcription initiation site. This nucleotide change predicts the nonsense mutation A alpha 149 Arg (CGA)-->stop (TGA). Early truncation of the A alpha chain appears to result in defective assembly or secretion of fibrinogen, probably due to the removal of the C-terminal disulfide ring residues that are critically required for the formation of a stable 3-chained half molecule. (Blood. 2000;96:773-775)

Adult↗
PubMed2000

Glucose intolerance in the polycystic ovary syndrome: role of the pancreatic beta-cell.

Women with polycystic ovary syndrome (PCOS) are at increased risk of developing diabetes mellitus type 2. Insulin resistance plays a key role in the predisposition to diabetes in PCOS; however, defects in insulin secretion also appear to contribute to its development. Since diabetes mellitus is not a universal consequence in PCOS, however, it is important to develop means to identify those women who are at highest risk. In this way, it may become possible to delay or even prevent the onset of diabetes mellitus in later life. Identification of genetic factors and use of pharmacological agents may allow early identification of those women with PCOS who are at greatest risk for development of diabetes mellitus type 2.

Dexamethasone↗
PubMed2001

[Diabetes mellitus].

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genetic factors contribute to the development of diabetes. Some forms such as the condition called maturity-onset diabetes of the young(MODY) result from mutations in a single gene. Other forms such as type 1 or type 2 diabetes are multifactorial in origin with different combinations of genes together with non-genetic factors contributing to the development of hyperglycemia. MODY has been a good model for studying the genetics and pathophysiology of diabetes. This form of diabetes can result from mutations in at least seven different genes: hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, HNF-1 alpha/MODY3, insulin promoter factor(IPF-1)/MODY4, HNF-1 beta/MODY5, NeuroD1/MODY6 and Islet(Isl)-1/MODY7. Mutations in HNF-1 alpha/MODY3 are the most common cause of MODY in Japanese identified to date accounting for about 15% of cases of MODY. Mutations in the HNF-4 alpha/MODY1, glucokinase/MODY2, HNF-1 beta/MODY5 and Isl-1/MODY7 genes have also been found in Japanese; however, they are rare causes of MODY. Clinical studies indicate that patients with MODY are generally not obese and that all forms of MODY are characterized by pancreatic beta-cell dysfunction. Patients who have mutations in the HNF-1 beta/MODY5 gene have non-diabetic kidney dysfunction including renal cysts. Female carriers may also exhibit abnormalities in the upper vagina and uterus. Genetic approach for type 2 diabetes had done by using non-parameteric linkage analysis such as sibpair analysis which worked well and NIDDM1 and NIDDM2 have been identified to date. The responsible gene for NIDDM1 was recently identified to be Calpain 10, and SNP43 in this gene could explain all of the evidence for linkage in Mexican American type 2 diabetes.

Diabetes Mellitus↗
PubMed2001

Gycemic control, mealtime glucose excursions, and diabetic complications in type 2 diabetes mellitus.

Type 2 diabetes mellitus is a heterogeneous disorder characterized by 2 pathogenic defects, impaired insulin secretion and insulin resistance. The resultant hyperglycemia causes microvascular and macrovascular complications that increase morbidity and mortality in patients with diabetes mellitus. Optimum glycemic control in patients with type 1 and type 2 diabetes mellitus prevents the development of microvascular disease and, to a lesser extent, macrovascular disease. Prandial hyperglycemia may be an independent risk factor for the development of diabetic complications. This article reviews the pathophysiologic mechanisms of glucose metabolism and describes the results of epidemiological and interventional studies that have demonstrated the association of acute and chronic hyperglycemia with the development of diabetic complications. The American Diabetes Association has defined diagnostic and treatment goals for diabetes mellitus, striving to achieve near-normal glycemic control to delay or prevent the development of diabetic complications. A number of oral antidiabetic agents and insulins are currently available for the treatment of type 2 diabetes mellitus in the United States. These agents target fasting and postmeal plasma glucose levels to improve glycemic control. Alone or in combination, these agents have enhanced the clinical approaches to treating diabetes mellitus.

Acute Disease↗
PubMed1979

[Pathogenesis of alcoholic liver injury (author's transl)].

The effects of ethanol on hepatic cellular metabolism and structure depend mainly on the dose and duration of intake. Following the ingestion of a substantial amount of ethanol, its presence alters a number of hepatic functions in part because of the change in the hepatic redox state (NADH/NAD ratio), resulting for instance in reduction of lipid oxidation. Furthermore, chronic ethanol consumption, at least in its early stages, produces adaptive metabolic changes in the endoplasmic reticulum which result not only in increased metabolism of drugs and accelerated lipoprotein production but also in activation of hepatotoxic compounds. Even more extended periods of ethanol intake result in damage to cell organelles in what can be considered a third stage of the alcohol effect namely that of injury. The injury involves primarily mitochondria, possibly as a consequence of effects of acetaldehyde, the first product of ethanol metabolism. Metabolites of ethanol also alter microtubular function. A defect in protein secretion may be the basis for protein retention and "ballooning" of the hepatocyte. Prolongation of ethanol induced injury eventually culminates in hepatic lesions such as alcoholic hepatitis and cirrhosis. Ethanol can be incriminated as a direct etiologic agent of the liver injury, since liver cirrhosis has been reproduced experimentally in baboons fed alcohol, despite an adequate diet.

Animals↗
PubMed1975

Evidence for permanent enhancement of residual ADH induced by antidiuretic agents (chlorpropamide, carbamazepine, clofibrate) in patients with pituitary diabetes insipidus.

Excretion of free water was studied in 7 patients with pituitary diabetes insipidus before treatment and after withdrawal of antidiuretic drugs (chlorpropamide, carbamazepine, clofibrate) used on a long-term basis. A statistically significant decrease in free water clearance was found after 2-4 weeks of withdrawal of antidiuretic agents. This was considered as a clinical evidence for the permanently enhanced release of residual ADH induced by chlorpropamide, carbamazepine and clofibrate in patients with partial defect in ADH secretion.

Adolescent↗
PubMedDate not supplied

Treatment strategies and new therapeutic advances for type 2 diabetes.

Because type 2 diabetes is caused by two defects, impaired insulin secretion and insulin resistance, logical management of diabetes will include combination therapies to treat this dual condition. Initial combination therapy should include an insulin secretagogue and an insulin sensitizer, with the addition of insulin in the evening if the HbA1c remains greater than 8%. Treatment to target should be clearly defined to achieve HbA1c < 7% unless there are specific individual considerations that make higher HbA1c levels acceptable or desirable. Patients are now treated earlier, when fasting blood glucose levels are in the 126 to 140 mg/dL range; and drugs with less chances of hypoglycemia are preferred at this stage. However, low-dose combination therapy as an early initial treatment, if HbA1c remains > 7%, is an emerging aggressive strategy that requires further consideration and further studies to prove its long-term efficacy and safety.

Biguanides↗