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 failure of some type I diabetic patients to secrete epinephrine and glucagon in response to hypoglycemia has been documented by many investigators, and most studies have confirmed that an inability to secrete these counterregulatory hormones places patients at risk for developing clinical hypoglycemia. Inadequate acute glucose counterregulation can result from multiple mechanisms. Failure of central glucoreceptors to recognize hypoglycemia and to activate counterregulation may be the most common. Decreased central recognition of hypoglycemia results from either strict antecedent glucose control or from a recent hypoglycemic event. Controversy about the relation between autonomic neuropathy and counterregulatory hormone secretion has arisen because divergent criteria have been used in the published studies for the diagnosis of autonomic neuropathy. Advanced adrenergic neuropathy, as evidenced by orthostatic hypotension, generally leads to decreased epinephrine secretion after hypoglycemia. Subclinical neuropathy, however, as diagnosed from measurement of heart rate variability, may diminish the awareness of hypoglycemia but does not affect counterregulatory hormone secretion. Failure of counterregulatory hormone secretion in some patients with type I diabetes, however, may represent a selective autonomic neuropathy; the disease has limited the patient's ability to secrete epinephrine and pancreatic polypeptide in response to hypoglycemia even though it has spared the autonomic neurons responsible for cardiovascular reflexes. Finally, recent provocative reports indicate that decreased responsiveness to adrenergic stimuli may cause hypoglycemia unawareness in some patients. Further documentation of this mechanism is required, and its relative importance with respect to other mechanisms needs to be established. These questions are increasingly important clinically because the Diabetes Control and Complications Trial has confirmed that the prevalence of severe hypoglycemia remains a major obstacle to attempts to prevent diabetic complications with intensive insulin therapy. Until glucose counterregulation is more fully understood and methods for preventing hypoglycemia developed, patients with recurrent hypoglycemia unawareness or a history of hypoglycemia-related accidents should probably not be treated with intensive insulin therapy.
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PMID:Epinephrine secretion, hypoglycemia unawareness, and diabetic autonomic neuropathy. 803 16

Impaired epinephrine secretion and symptom unawareness are characteristic of severe hypoglycemia in individuals with long-standing type I diabetes. Recently, the avoidance of clinical hypoglycemia has been reported to improve epinephrine and symptom responses to hypoglycemia in type I patients. However, the extent to which these defects can be restored in individuals with long-standing type I diabetes and autonomic neuropathy has not been assessed, nor has it been determined whether pancreas transplantation, which not only obviates hypoglycemia but also prevents hyperglycemia, results in the complete recovery of either epinephrine response or symptom awareness during insulin-induced hypoglycemia. We performed stepped hypoglycemic clamp studies in successful pancreas transplantation recipients to assess epinephrine and other counterregulatory hormone responses during hypoglycemia and to determine the degree to which hypoglycemic symptom recognition could be restored. Thirteen pancreas transplant recipients and matched control subjects were studied utilizing stepped hypoglycemic clamp protocol to achieve target glucose levels of 3.9, 3.3, 2.8, and 2.2 mmol/l (70, 60, 50, and 40 mg/dl, respectively). Plasma epinephrine response was significantly greater in healthy control subjects and pancreas transplant patients compared with type I subjects at the glucose plateaus of 3.9, 3.3, and 2.8 mmol/l. However, epinephrine response in pancreas transplant recipients was significantly less than that seen in either healthy control subjects or nondiabetic kidney transplant recipients at each of these glucose plateaus. The magnitude of the epinephrine response in pancreas transplant type I patients did not correlate with either the duration of diabetes, the duration of transplantation, or the measures of autonomic nerve function. Hypoglycemic symptom recognition was significantly greater in pancreas transplant subjects than type I patients and did not differ between pancreas transplant and control groups. No improvement in norepinephrine response was observed after pancreas transplantation, while glucagon responses to hypoglycemia were normalized in pancreas transplant patients. In conclusion, these studies uniquely demonstrate that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long-standing diabetes and established autonomic neuropathy. No correlation was observed between the severity of autonomic neuropathy or the duration of diabetes and the recovery of either the epinephrine or symptom responses to hypoglycemia.
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PMID:Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. 900 Jul 2

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxylase (GAD) has been described in a substantial proportion of patients with insulin-dependent diabetes mellitus (IDDM) of long duration. The source of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cells and in the nervous system we investigated in the present study of the largest number of well characterized patients with longstanding IDDM (n = 105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-peptide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of the 105 individuals. One hundred healthy control subjects and 100 recent onset IDDM patients were also studied for GAD 65 antibodies. GAD 65 antibodies were detected in a radioligand-binding-assay with recombinant human GAD 65 and were present in 32% of the long-term diabetic patients, 82% of the recent onset IDDM patients and in 3% of the healthy control subjects. A preserved C-peptide response to i.v. glucagon (Hendriksen criteria) was observed in 23% of the long-term IDDM patients. Autonomic neuropathy and peripheral neuropathy was identified using criteria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients. Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were significantly less frequent in the long-term IDDM patients compared to recent onset IDDM (p < 0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r = 0.22, p < 0.01). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particular HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persistent autoimmunity directed to GAD 65 in longstanding IDDM. The stimulus for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.
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PMID:Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status. 940 79

The purpose of the study was to investigate the effects of octreotide on the response of counterregulatory hormones to insulin-induced hypoglycaemia in 9 Type 1 diabetic patients without autonomic neuropathy. During an euglycaemic clamp, saline or octreotide (50 mcg) was randomly injected subcutaneously. Patients were then clamped to hypoglycaemic levels (2.5 mmol/l), and hormonal response was evaluated after 30 min of hypoglycaemia. Although octreotide suppressed both GH (0.5 +/- 0.01 vs 9.5 +/- 0.9 ng/ml, p < 0.001) and glucagon (110 +/- 9 vs 165 +/- 10 pg/ml, p < 0.05) responses, it did not affect cortisol, epinephrine, IGF-1 and IGFBP-3 levels. The time required for recovery from hypoglycaemia was longer after octreotide (19.1 +/- 1.2 min vs 14.3 +/- 0.9 min, p < 0.05), and a greater amount of infused glucose was needed to reach normoglycaemia (g 24.6 +/- 1.2 vs 17.7 +/- 1.3, p < 0.05). These findings suggest that administration of octreotide to insulin-treated Type 1 diabetic patients may impair anti-hypoglycaemic counterregulatory mechanisms through suppression of glucagon and GH responses.
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PMID:Effect of octreotide on growth hormone, IGF-I, IGFBP-3, glucagon, cortisol and epinephrine response to insulin-induced hypoglycaemia in insulin-dependent diabetic patients. 949 59

Palatable cephalic stimuli induce a simultaneous activation of gastrointestinal motility, gastric acid and pancreatic enzyme secretion, as well as, release of the gastrointestinal hormones gastrin and pancreatic polypeptide. Cholinergic neural input is the dominant mediator of these responses with cholecystokinin and gastrin acting as additional stimulatory modulators. Central cholinergic circuits, neuropeptide Y, and thyrotropin releasing hormone are candidate central stimulators of the cephalic phase. There are good arguments for glucagon-like peptide-1 and peptide YY to be physiological inhibitors of cephalic-phase responses with these peptides being released in the intestinal phase of digestion and putatively contributing to termination of the cephalically stimulated pattern. Cephalic-phase responses are used clinically as diagnostic tests to assess completeness of selective proximal vagotomy and to explore autonomic neuropathy. Pancreatic polypeptide secretion with sham feeding is an appropriate test of abdominal vagal function. Cephalically stimulated motor and secretory activity contribute greater than 50% of overall postprandial responses. Pharmacological inhibition of cephalic-vagal stimulation, resulting in reduced food intake, may be a novel approach to obesity management. Glucagon-like peptide-1 is a particular candidate because it inhibits the cephalic phase of digestion, diminishes food intake, and reduces the glycemic excursion after a meal by retarding gastric emptying, stimulating insulin and lowering glucagon release.
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PMID:Nutritional implications of cephalic phase gastrointestinal responses. 1074 9

A marked sexual dimorphism in neuroendocrine and metabolic responses to moderate, prolonged exercise occurs in healthy humans. It is unknown whether similar differences occur in type 1 diabetes mellitus (T1DM). Fifteen patients with T1DM (7 women and 8 men) were studied during 90 min of euglycemic exercise at 50% of the maximum rate of O(2) consumption. Men and women were matched for age, glycemic control, duration of diabetes, and exercise fitness, and had no history or evidence of autonomic neuropathy. Hypoglycemia was scrupulously avoided during the week preceding tests. Exercise was performed under constant infusion of regular insulin (1 U/h) and a variable 20% dextrose infusion, as needed to maintain euglycemia. At 15-min intervals, neuroendocrine, metabolic (glucose kinetics, intermediate metabolism, lipolysis), and cardiovascular responses were assessed. Indirect calorimetry was performed during the last 10 min of exercise. Plasma glucose and insulin did not differ between genders at baseline or during exercise. Key neuroendocrine responses were significantly reduced in women, compared with men, during exercise (epinephrine, 360 +/- 104 vs. 666 +/- 126 pM; norepinephrine, 2.3 +/- 0.8 vs. 4.1 +/- 1.0 nM; GH, 10 +/- 5 vs. 22 +/- 8 micro g/liter). Glucagon, cortisol, and pancreatic polypeptide responses were similar between genders. Despite reduced catecholamine responses in women, no gender differences were observed in endogenous glucose production (EGP) or exogenous glucose infusion rate during exercise. The lipolytic response to exercise (blood glycerol), on the other hand, was greater in women than in men. In conclusion, a marked sexual dimorphism exists in counterregulatory responses to exercise in T1DM, including key neuroendocrine (catecholamine, GH) and metabolic (lipolysis) responses. Other responses, including glucagon and EGP, were similar between genders, suggesting that the glucagon to insulin ratio may be the primary determinant of EGP during moderate intensity exercise in T1DM.
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PMID:Effect of gender on counterregulatory responses to euglycemic exercise in type 1 diabetes. 1241 85

A marked sexual dimorphism exists in healthy individuals in the pattern of blunted neuroendocrine and metabolic responses following antecedent stress. It is unknown whether significant sex-related counterregulatory differences occur during prolonged moderate exercise after antecedent hypoglycemia in type 1 diabetes mellitus (T1DM). Fourteen patients with T1DM (7 women and 7 men) were studied during 90 min of euglycemic exercise at 50% maximal O(2) consumption after two 2-h episodes of previous-day euglycemia (5.0 mmol/l) or hypoglycemia of 2.9 mmol/l. Men and women were matched for age, glycemic control, duration of diabetes, and exercise fitness and had no history or evidence of autonomic neuropathy. Exercise was performed during constant "basal" intravenous infusion of regular insulin (1 U/h) and a 20% dextrose infusion, as needed to maintain euglycemia. Plasma glucose and insulin levels were equivalent in men and women during all exercise and glucose clamp studies. Antecedent hypoglycemia produced a relatively greater (P < 0.05) reduction of glucagon, epinephrine, norepinephrine, growth hormone, and metabolic (glucose kinetics) responses in men compared with women during next-day exercise. After antecedent hypoglycemia, endogenous glucose production (EGP) was significantly reduced in men only, paralleling a reduction in the glucagon-to-insulin ratio and catecholamine responses. In conclusion, a marked sexual dimorphism exists in a wide spectrum of blunted counterregulatory responses to exercise in T1DM after prior hypoglycemia. Key neuroendocrine (glucagon, catecholamines) and metabolic (EGP) homeostatic responses were better preserved during exercise in T1DM women after antecedent hypoglycemia. Preserved counterregulatory responses during exercise in T1DM women may confer greater protection against hypoglycemia than in men with T1DM.
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PMID:Effect of sex on counterregulatory responses to exercise after antecedent hypoglycemia in type 1 diabetes. 1499 85

Type 1 diabetes is an intrinsically unstable condition. However, the term "brittle diabetes" is reserved for those cases in which the instability, whatever its cause, results in disruption of life and often recurrent and/or prolonged hospitalization. It affects 3/1000 insulin-dependent diabetic patients, mainly young women. Its prognosis is poor with lower quality of life scores, more microvascular and pregnancy complications and shortened life expectancy. Three forms have been described: recurrent diabetic ketoacidosis, predominant hypoglycemic forms and mixed instability. Main causes of brittleness include malabsorption, certain drugs (alcohol, antipsychotics), defective insulin absorption or degradation, defect of hyperglycemic hormones especially glucocorticoid and glucagon, and above all delayed gastric emptying as a result of autonomic neuropathy. Psychosocial factors are very important and factitious brittleness may lead to a self-perpetuating condition. The assessment of brittle diabetes requires quantification of the variability of blood glucose levels. To quantify instability, measures which have been developed, include Mean Amplitude of the largest Glycemic Excursions (MAGE), Mean Of Daily Differences (MODD), Lability Index (LI), Low Blood Glucose Index (LBGI), Clarke's score, Hyposcore, and continuous blood glucose monitoring. Once psychogenic problems have been excluded, therapeutic strategies require firstly, the treatment of underlying organic causes of the brittleness whenever possible and secondly optimising standard insulin therapy using analogues, multiple injections and consideration of Continuous Subcutaneous Insulin Infusion. Alternative approaches may still be needed for the most severely affected patients. Isolated islet transplantation (IIT), which restores glucose sensing, should be considered in cases of hypoglycaemic unawareness and/or lability especially if the body mass index is < 25, but with current immunosuppressive protocols patients must have normal renal function and preferably no plans for pregnancy. Implantable pumps have advantages for patients who either weigh more than 80 kgs or have abnormalities of kidney or liver function or are highly sensitised.
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PMID:Management strategies for brittle diabetes. 1707 32

Heart rate (HR) predicts cardiovascular morbidity and mortality in individuals either with or without diabetes. In type 2 diabetic patients, cardiac autonomic neuropathy is a risk marker for cardiac morbidity and mortality. A major pathogenic potential may be attributed to vagal depression and sympathetic predominance. In this issue of Diabetologia, Berkelaar et al (DOI: 10.1007/s00125-013-2848-6 ) examined the effects of euglycaemic, and hyperglycaemic clamp with the addition of glucagon-like-peptide-1 (GLP-1) and arginine, on cardiac vagal control in a large number of healthy subjects. After adjustments for age, BMI and insulin sensitivity, insulin associations with HR remained partially intact while those with vagal control disappeared. This suggested that BMI and insulin sensitivity, but not insulin levels, were the main drivers of cardiac vagal control. GLP-1 infusion during hyperglycaemia increased HR and BP and produced a statistically non-significant decrease in measures of cardiac vagal control compared with values before any manipulation of insulin levels. This commentary summarises how, and to what extent, insulin and GLP-1 affect autonomic nervous system activity, HR and BP. More information is needed on the mechanisms through which acute administration of, and long-term treatment with, GLP-1 may affect haemodynamics and autonomic activity in diabetic and obese patients, since this may influence cardiovascular outcomes.
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PMID:Insulin- and glucagon-like peptide-1-induced changes in heart rate and vagosympathetic activity: why they matter. 2340 43

An important obstacle to achieve optimal glycaemic control in diabetics on intensive insulin therapy is the frequent occurrence of insulin induced hypoglycaemic events. In healthy subjects and in diabetics without autonomic neuropathy hypoglycaemia activates the sympathetic nervous system, resulting in epinephrine and glucagon release. Both hormones increase hepatic glucose production and this counterregulatory response is of key importance of glucose homeostasis. Recent research shed light on the fact that antecedent hypoglycaemic episodes play pivotal role in hypoglycaemia associated autonomic failure (HAAF). In this condition the sympatho-adrenal response to decreased blood glucose level is blunted. The existence of HAAF clearly indicates that the nervous system contributes to glucose homeostasis in a substantial manner. This review outlines the mechanisms of both peripheral and central neuronal glucose sensing and of neural pathways involved in the counterregulatory response.
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PMID:Brain glucose sensing and counterregulatory response to hypoglycaemia. 2370 45


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