Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The classification of adults with diabetes mellitus can be invalidated by patients who initially present as NIDDM but who later become frankly insulin dependent. In some of these, the pathogenesis could be similar to that in IDDM, namely autoimmune destruction of the pancreatic beta-cells. We studied 102 patients > 35 yr of age at diabetes onset who had initially been nonketotic and non-insulin-dependent for > or = 6 mo. They were classified according to glucagon-stimulated C-peptide levels into an insulin-deficient group (n = 33) and a non-insulin-deficient group (n = 69). We measured antibodies to GAD, islet cell cytoplasm, thyroid antigens, and gastric parietal cells in both groups. Anti-GAD was significantly higher in the insulin deficient group, 76% (25 of 33), than in the non-insulin deficient group, 12% (8 of 69), and this difference was substantially greater than that shown for ICAs. Thus, in a proportion of adults who present with NIDDM, a slowly evolving autoimmune insulitis can be revealed by testing for anti-GAD. This could have important connotations not only for early intervention, but also for the correct classification of diabetes.
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PMID:Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. 842 74

IDDM subjects lose the ability to release glucagon during hypoglycemia. Because replacement of basal levels of amino acids enhances the glucagon response to hypoglycemia in healthy subjects, we tested whether raising amino acid levels during hypoglycemia could reverse the defective alpha-cell response in IDDM patients. For this purpose, 11 IDDM patients (HbA1 9.4 +/- 0.6%) and 8 healthy, nondiabetic subjects received two hypoglycemic insulin clamp studies (0.8 mU.kg-1 x min-1) in which plasma glucose was clamped at 55 mg/dl (3.08 mM) for 180 min. During one of the studies, an infusion of amino acids was superimposed between 120 and 180 min (0.3 g.kg-1 x h-1). This dose of amino acids had a small effect on plasma glucagon levels during euglycemic hyperinsulinemia that was comparable in normal and IDDM subjects. In healthy control subjects, plasma glucagon rose by 80% during the initial hypoglycemic phase of the study. The addition of amino acids produced a further sharp (200-250 ng/L, P < 0.02) rise in plasma glucagon, such a change did not occur in the absence of amino acids. In contrast, plasma glucagon in IDDM patients failed to increase during hypoglycemia alone and rose by only 40-50 ng/L (P < 0.05 vs. controls) when amino acid infusion was superimposed, even though plasma amino acid levels rose to the same extent in IDDM and control subjects. More importantly, the rise in glucagon produced by amino acids was comparable during hypoglycemic and euglycemic hyperinsulinemia in the IDDM patients, results strikingly different from those observed in nondiabetic control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Loss of potentiating effect of hypoglycemia on the glucagon response to hyperaminoacidemia in IDDM. 845 5

Biosynthetic glucagon (GL-G) produced by recombinant DNA technology with transformed yeast strains is already available for clinical use. We studied the effects of 1 mg GL-G injection on plasma glucose level and hypoglycemic symptoms in 38 diabetic patients treated with insulin or oral hypoglycemic agents during spontaneous hypoglycemic episodes. In both intramuscularly and intravenously administered GL-G groups, plasma glucose significantly increased from 58.1 +/- 11.4 to 113.2 +/- 6.9 mg/dl (i.m., n = 17, P < 0.01) and from 76.4 +/- 4.4 to 125.7 +/- 5.9 mg/dl (i.v., n = 15, P < 0.01), respectively 20 min after the administration and the symptoms due to hypoglycemia subsided promptly after the injection of GL-G in 27 cases. The hyperglycemic effect of intramuscularly injected GL-G was more potent and long-standing than when intravenously injected, particularly in insulin-dependent diabetic (IDDM) patients. Neither significant changes of antibody levels against yeast proteins nor serious adverse effects were observed after GL-G administration. Biosynthetic glucagon is safe and useful for the treatment of hypoglycemia developing in diabetic patients.
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PMID:Clinical evaluation of biosynthetic glucagon treatment for recovery from hypoglycemia developed in diabetic patients. The GL-G Hypoglycemia Study Group. 847 28

We evaluated the effect of physiologic hyperinsulinemia (plasma insulin 329 +/- 62 vs 687 +/- 62 pmol/L) on counterregulatory hormone responses in 8 IDDM subjects studied during a 2-hour hypoglycemic clamp study with an equivalent degree of hypoglycemia (plasma glucose 3.1 +/- 0.1 and 3.0 +/- 0.1 mmol/L, respectively). Plasma epinephrine levels were increased by 71% during the last 60 minutes of hypoglycemia in the high insulin study (840 +/- 180 vs 1440 +/- 310 pmol/L, respectively p = 0.006). In addition, plasma cortisol and norepinephrine were also increased in the high insulin study (by 19% and 24% respectively, p < 0.01, for both). Plasma growth hormone and glucagon concentrations were not altered by high dose insulin infusion. In spite of increased epinephrine secretion, the glucose infusion rate required to maintain glucose was 2-fold greater in the high insulin study, and there was greater suppression of lipolysis in that group. We conclude that hyperinsulinemia may enhance counterregulatory hormone secretion in IDDM.
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PMID:Physiologic hyperinsulinemia enhances counterregulatory hormone responses to hypoglycemia in IDDM. 849 33

In juvenile IDDM patients, immunosuppression with cyclosporin A allows partial beta-cell function recovery and transient remissions of insulin dependency. The effects of this therapeutic approach, however, have not been evaluated in the long-term, since no reported trial exceeded 1 year. Here we analyze 130 diabetic children followed at our institution during the first years of their disease. Cyclosporin was given to 83 of them at an initial dose of 7.2 +/- 0.1 mg.kg-1.day-1, which was decreased stepwise then interrupted after 6-62 months, depending on the response to therapy. A total of 47 diabetic children, who served as control subjects in two trials, were pooled for comparison. Over 4 years, the cyclosporin-treated group kept plasma C-peptide approximately twice as high as the control group (P < 0.02). It took 5.8 +/- 0.6 years for C-peptide secretion stimulated by glucagon to become undetectable in the cyclosporin group versus 3.2 +/- 0.6 years in the control group (P < 0.02). Average insulin dose remained lower by 0.2-0.4 U.kg-1.day-1 and glycated hemoglobin by approximately 1% in cyclosporin-treated patients (P < 0.02), who also had less hypoglycemia than the diabetic control subjects (P < 0.05). After 4 years, differences between the groups became nonsignificant. We observed no significant secondary effects of cyclosporin. In conclusion, positive effects of low-dose cyclosporin in recently diagnosed clinical IDDM patients are prolonged beyond interruption of the drug. The magnitude and duration of the benefit, however, do not appear sufficient to justify this immunosuppressive treatment in clinical practice.
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PMID:Long-term results of early cyclosporin therapy in juvenile IDDM. 852 52

Most of diabetics have no symptoms and chemical analyses may be sole way to diagnose the disease itself and its complications. Chemical analyses are also important to assess the propriety of glycemic control during every possible treatment of diabetes. Some markers for long-term glycemic control other than glucose concentration may be also used as a screening methods for glucose intolerance. HbA1c is established for long term as a marker for glycemic control but still large interlaboratory variation is present. Fructosamine is measured by a simpler procedure but many deoxidizing materials in serum especially superoxide may interfere with the reaction. Glycated albumin should be more reliable than fructosamine but a standard method of measurement has not been established yet. The decrease in serum 1,5-anhydro-D-glucitol(1,5-AG) is very sensitive to urinary glucose excretion and may be useful as a marker of glycemic control and diagnosis of diabetes. Discrimination of Type I(IDDM) from Type II(NIDDM) in Japanese diabetic patients is sometimes very difficult and evidences of autoimmunity by anti-glutamic acid decarboxylase(GAD) antibody and of exhaustion of insulin secretion by C-peptide measurement 6min after combined infusion of 1mg of glucagon and 20ml of 50% glucose are the few methods to diagnose. Early diagnosis of diabetic complication is another important point of clinico-chemical determinations. Usually, each diabetic complication progresses in parallel. Micro-measurement of urinary transferrin is one of the most sensitive methods likewise urinary microalbumin measurement. Future measurement of advanced glycation end product (AGE) may also tell us if patients are suffering from diabetic complications or if one is suffering from diabetes or not.
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PMID:[Recent progress in diagnoses of diabetes and its complications]. 856 34

The present study examines the effect of the route of insulin delivery on glucose turnover in humans. By using a new noninvasive in vivo method, the acute effect of insulin secreted by the pancreas can be compared with that of insulin delivered by a peripheral vein. Three euglycemic-hyperinsulinemic studies were performed in lean healthy men. In the first study (n = 10), constant portal hyperinsulinemia was produced using a programmed intravenous tolbutamide infusion algorithm, and the insulin secretion rate was mathematically derived by deconvolution from peripheral plasma C-peptide levels. In the second study (n = 10), exogenous insulin was infused by peripheral vein at the same rate as that determined in the first study. In the third study (n = 7), the peripheral insulin levels in the first study were matched by infusing exogenous insulin into a peripheral vein at half that rate. Peripheral insulin levels were higher (P < 0.001) with the full-rate peripheral insulin infusion (266.3 +/- 28.1 pmol/l) than with the portal delivery of insulin (171.1 +/- 30.4 pmol/l) or the half-rate peripheral insulin infusion (158.6 +/- 7.4 pmol/l) (portal versus half-rate peripheral insulin infusion, NS). Calculated hepatic insulin levels were higher (P < 0.001) in the portal insulin study (443.1 +/- 52.6 pmol/l) than in the full-rate peripheral insulin study (303.6 +/- 30.9 pmol/l) or in the half-rate peripheral insulin study (204.5 +/- 9.8 pmol/l). Hepatic glucose production (HGP) was suppressed to a greater extent with the full-rate peripheral insulin infusion (69.3 +/- 7.8%, P < 0.001 vs. portal or half-rate peripheral insulin) than portal (50.3 +/- 9.8%) or half-rate peripheral insulin infusion (36.8 +/- 3.8%). In the portal insulin study, however, suppression was greater than in the half-rate peripheral insulin study (P < 0.01), in spite of equal peripheral insulin levels. The assumption that tolbutamide, when used in this fashion, has no independent effect on glucose turnover, glucagon, or gluconeogenic precursor and energy substrates for gluconeogenesis was validated in five C-peptide-negative patients with IDDM. We conclude that in nondiabetic humans, 1) peripheral effects of insulin are important in suppressing HGP, as evidenced by the greater suppression of HGP with equivalent rate peripheral versus portal insulin delivery, and 2) because HGP was suppressed to a greater extent with portal verus peripheral insulin delivery at half the rate when peripheral insulin levels were matched, insulin-induced suppression of HGP is also partly mediated by a direct hepatic effect.
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PMID:Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans. 860 67

One of the major beta-cell autoantigens associated with IDDM is GAD. Although GAD expression has been detected in adult islets, transcriptional expression of the GAD genes has not been reported during human pancreatic ontogeny. We therefore analyzed patterns of GAD gene transcription by quantitating the mRNAs encoding both the 65- and 67-kDa isoforms (GAD65 and GAD67, respectively) in human fetal, postnatal, and adult pancreases, as well as in isolated adult islets, and examined their tissue-specific expression. Significant levels of pancreatic GAD65 transcripts were already detected at 13 weeks of gestation and were expressed at higher levels in the fetal and infantile pancreas than in the adult pancreas. Isolated adult pancreatic islets were highly enriched in GAD65 mRNA. In contrast, GAD67 transcripts were not detectable in fetal and postnatal pancreases. In addition to the pancreas, marked GAD expression was detected in the brain, whereas other tissues examined contained either low or undetectable GAD transcripts. Triple immunofluorescent staining of fetal and adult pancreases revealed colocalization of GAD65 with alpha- and beta-cells. In the fetal pancreas, strong immunoreactivity for GAD65 was also evident in epithelial cells, which lacked expression of insulin or glucagon, some of which were present in the ductal epithelium, suggesting that GAD65 expression might correlate with endocrine determination. In summary, 1) this is the first demonstration of GAD65 expression in the human fetal pancreas, implicating a potential role during islet development, and 2) GAD65 may be a useful marker for the identification of primitive islet cells.
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PMID:Ontogeny and tissue distribution of human GAD expression. 860 72

In IDDM, the gluconeogenic turnover of amino acids is increased even if glycemia is well controlled and may be restored to normal by means of prehepatic insulin substitution. Therefore, the present study was designed 1) to investigate the influence of route of insulin administration (portal versus peripheral) on the urea production rate, which is considered to measure amino acid catabolism, and 2) to elucidate the impact of different food-protein intake. Paired studies were conducted in chronic insulin-dependent diabetic dogs maintained normoglycemic. Diabetic animals and nondiabetic controls were fed either a high-protein diet (46% of energy intake provided by proteins; study 1) or a low-protein carbohydrate-supplemented diet (20% of energy intake provided by protein; study 2) for 2 days, and flux rates of glucose and urea were measured using isotope dilution techniques. In both studies, the diabetic animals were maintained normoglycemic by glucose-controlled insulin infusion delivered either systemically or portally. In study 1 versus study 2, the animals showed lower alpha-amino nitrogen levels and concentrations of gluconeogenic amino acids, predominantly alanine. There were no significant differences in plasma glucose and glucose turnover between the experimental groups on either systemic or portal insulin infusion versus controls; however, peripheral insulin levels were higher for diabetic animals maintained with systemic versus portal insulin delivery (P < 0.05). No significant differences in glucagon, lactate, pyruvate, nonesterified fatty acids, or beta-hydroxybutyrate were observed. Urea production was significantly higher in study 1 compared with study 2: 7.48 +/- 0.83 vs. 5.97 +/- 0.59 micromol / kg / min (normal dogs); 12.97 +/- 1.86 vs. 5.54 +/- 0.60 micromol / kg / min (diabetic dogs on portal insulin); 16.11 +/- 2.59 vs. 6.82 +/- 0.70 micromol / kg / min (diabetic dogs on systemic insulin infusion); P < 0.05 for all. The diabetic dogs maintained normoglycemic with systemic insulin infusions had significantly higher rates of urea synthesis than those with portal insulin infusion (P < 0.05). It is concluded that in IDDM, even if normoglycemia is managed, there is significantly increased amino acid catabolism with posthepatic systemic insulin treatment. This increased catabolic rate is more pronounced during high-protein nourishment.
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PMID:Increased urea synthesis in insulin-dependent diabetic dogs maintained normoglycemic: effect of portal insulin administration and food protein content. 862 Oct 20

Iatrogenic hypoglycemia is a major problem for patients with IDDM. The principles of glucose counterregulation, the physiological mechanisms that normally prevent or correct hypoglycemia, are now known. In concert with decrements in insulin, increments in glucagon, and in the absence of the latter increments in epinephrine, stand high in the hierarchy of redundant glucose counterregulatory factors. In IDDM, iatrogenic hypoglycemia is the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation. Syndromes of compromised glucose counterregulation include hypoglycemia unawareness (loss of the warning, neurogenic symptoms of developing hypoglycemia), defective glucose counterregulation (the result of combined deficiencies of the glucagon and epinephrine responses to falling glucose levels), and elevated glycemic thresholds (lower glucose levels required) for autonomic activation and symptoms during effective intensive therapy. These have been conceptualized as examples of hypoglycemia-associated autonomic failure. Hypoglycemia unawareness, but not defective glucose counterregulation, is reversible during scrupulous avoidance of iatrogenic hypoglycemia. Clearly, we need to learn to replace insulin in a much more physiological fashion, or to prevent, correct, or compensate for compromised glucose counterregulation, or both, if we are to eliminate hypoglycemia from the lives of people with IDDM without compromising glycemia control. In the meantime we must practice hypoglycemia risk factor reduction with our patients, continue to seek better insight into the fundamental mechanisms of compromised glucose counterregulation, and develop practical preventive clinical strategies.
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PMID:Hypoglycemia-induced autonomic failure in insulin-dependent diabetes mellitus. 863 Jul 45


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