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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Given that iatrogenic hypoglycemia often occurs during the night in people with type 1 diabetes, we tested the hypothesis that physiological, and the resulting behavioral, defenses against developing hypoglycemia-already compromised by absent glucagon and attenuated epinephrine and neurogenic symptom responses-are further compromised during sleep in type 1 diabetes. To do so, we studied eight adult patients with uncomplicated type 1 diabetes and eight matched nondiabetic control subjects with hyperinsulinemic stepped hypoglycemic clamps (glucose steps of approximately 85, 75, 65, 55, and 45 mg/dl) in the morning (0730-1230) while awake and at night (2100-0200) while awake throughout and while asleep from 0000 to 0200 in random sequence. Plasma epinephrine (P = 0.0010), perhaps norepinephrine (P = 0.0838), and pancreatic polypeptide (P = 0.0034) responses to hypoglycemia were reduced during sleep in diabetic subjects (the final awake versus asleep values were 240 +/- 86 and 85 +/- 47, 205 +/- 24 and 148 +/- 17, and 197 +/- 45 and 118 +/- 31 pg/ml, respectively), but not in the control subjects. The diabetic subjects exhibited markedly reduced awakening from sleep during hypoglycemia. Sleep efficiency (percent time asleep) was 77 +/- 18% in the diabetic subjects, but only 26 +/- 8% (P = 0.0109) in the control subjects late in the 45-mg/dl hypoglycemic steps. We conclude that autonomic responses to hypoglycemia are reduced during sleep in type 1 diabetes, and that, probably because of their reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia. Thus both physiological and behavioral defenses are further compromised during sleep. This sleep-related hypoglycemia-associated autonomic failure, in the context of imperfect insulin replacement, likely explains the high frequency of nocturnal hypoglycemia in type 1 diabetes.
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PMID:Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. 1271 52

Plasma counterregulatory hormones and symptoms were measured during hypoglycemia in the postprandial and in the fasting state in humans to establish differences in physiological responses. We studied 8 nondiabetic subjects and 10 subjects with type 1 diabetes on two different occasions during clamped insulin-induced hypoglycemia (2.4 mmol/l) in the sitting position. On one occasion, subjects ate a standard mixed meal, and on the other they remained fasting. In response to postprandial as compared with fasting hypoglycemia, nondiabetic subjects exhibited lower total symptom scores (6.6 +/- 0.4 vs. 11.5 +/- 0.8, P = 0.001), which was due to less hunger (1.1 +/- 0.1 vs. 4.2 +/- 0.2), lower suppression of plasma C-peptide (0.23 +/- 0.1 vs. 0.08 +/- 0.07 nmol/l, P = 0.032), and greater responses of plasma glucagon (248 +/- 29 vs. 163 +/- 25 ng x l(-1) x min(-1), P = 0.018), plasma adrenaline (4.5 +/- 0.6 vs. 3.1 +/- 0.4 nmol x l(-1) x min(-1), P = 0.037), norepinephrine (3.8 +/- 0.3 vs. 3.2 +/- 0.2 nmol x l(-1) x min(-1), P = 0.037), and pancreatic polypeptide (217 +/- 12 vs. 159 +/- 22 pmol x l(-1) x min(-1), P = 0.08). Except for plasma C-peptide, responses in diabetic subjects were similarly affected. Notably, in diabetic subjects responses of glucagon, which were absent in the fasting state, nearly normalized after a meal. In conclusion, in the postprandial compared with the fasting hypoglycemic state, total symptoms are less, but counterregulatory hormones are greater and responses of glucagon nearly normalize in type 1 diabetic subjects.
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PMID:Counterregulatory hormone and symptom responses to insulin-induced hypoglycemia in the postprandial state in humans. 1457 96

Antecedent moderate-intensity exercise has been shown to blunt autonomic, neuroendocrine, and metabolic counterregulatory responses to subsequent hypoglycemia in nondiabetic individuals. The aims of the current study were to determine 1) whether this occurs in type 1 diabetic patients and 2) whether the degree of blunting is dependent on exercise intensity. Twenty-seven type 1 diabetic patients (13 women and 14 men) were studied during a single-step, 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1))-hypoglycemic (approximately 2.8 mmol/l) clamp 1 day after two 90-min exercise bouts at 30% (n = 11) or at 50% (n = 11) Vo(2max) or after no prior stress (control subjects, n = 25). After prior exercise at both 30 and 50% Vo(2max), epinephrine (1,959 +/- 553 and 1,528 +/- 424 vs. 3,420 +/- 424 pmol/l, respectively; P < 0.05) and pancreatic polypeptide (97 +/- 32 and 98 +/- 8 vs. 223 +/- 32 pmol/l, respectively; P < 0.05) responses to subsequent hypoglycemia were significantly lower compared with those of control subjects. Endogenous glucose production was significantly lower, while glucose utilization and, consequently, the exogenous glucose infusion rate needed to maintain hypoglycemia were significantly greater after both exercise intensities compared with that of control subjects. Muscle sympathetic nerve activity was significantly reduced by prior exercise of both intensities at baseline (16 +/- 4 and 22 +/- 4 vs. 31 +/- 3 bursts/min) and during hypoglycemia (22 +/- 4 and 27 +/- 5 vs. 41 +/- 3 bursts/min) compared with that of control subjects (P < 0.05). Total hypoglycemic symptoms were also significantly lower (P < 0.05) in both exercise groups compared with the control group. In summary, repeated episodes of prolonged exercise of both low and moderate intensities blunted key autonomic (epinephrine and pancreatic polypeptide) and metabolic (endogenous glucose production and peripheral glucose uptake) counterregulatory responses to next-day hypoglycemia in type 1 diabetes.
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PMID:Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes. 1522 Feb 4

Exendin-4 is a reptilian peptide that activates the mammalian receptor for truncated glucagon-like peptide 1 (tGLP-1) with relatively prolonged actions. Exendin-4 and tGLP-1 can reduce blood glucose levels by stimulating insulin secretion, inhibiting glucagon secretion, and delaying gastric emptying. We tested a range of doses of exendin-4 on postcibal glycemic excursions in nine volunteers with type 1 diabetes, all with negligible endogenous insulin secretion, in paired comparisons with vehicle in at least six volunteers with each of six doses. We established a side effect-free dose and an appropriate antecibal time for sc administration of exendin-4. Subsequently, exendin-4 was administered 15 min before breakfast, with usual insulin, to eight of the volunteers. Acetaminophen was ingested with the meal as an indicator of gastric emptying. The mean plasma glucose excursion was reduced by 90%, falling into the normal range, after breakfast, whereas plasma pancreatic polypeptide, glucagon, and acetaminophen levels were reduced, and insulin levels were not affected. Thus, normalization of postcibal glycemia was associated with delayed gastric emptying and suppression of glucagon secretion, without increased secretion or blood levels of insulin. We suggest that tGLP-1 agonists have therapeutic potential as congeners with insulin in C-peptide-negative type 1 diabetes.
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PMID:Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. 1524 Jun 33

The remission phase of Type 1 diabetes mellitus is associated with substantial recovery of beta-cell function and with marked improvement of endogenous insulin responses to meals in the early months after diagnosis, accompanied by little or no improvement in the insulin response to parenteral glucose, suggesting that the incretin function may be important in glycaemic regulation in this phase of diabetes. Preservation of the insulin response to parenteral glucagon-like peptide-1 (GLP-1), contrasting with lack of stimulation of insulin secretion by the other known incretin gastric inhibitory polypeptide (GIP), prompted studies with exogenous GLP-1 in recent-onset Type 1 diabetes. These studies showed substantial reduction of glycaemic excursions after ingestion of mixed nutrients during intravenous infusion of GLP-1 without administration of insulin, in subjects with a range of endogenous secretion of insulin in response to meals as demonstrated by blood levels of the insulin-connecting peptide (CP). These effects were independent of stimulation of blood levels of CP and were reproduced in volunteers with no endogenous release of CP in response to meals. The glycaemic effects were associated with inhibition of abnormal rises of blood levels of glucagon, and with suppression of endogenous release of human pancreatic polypeptide (HPP), by GLP-1. It was hypothesized that a major component of the glycaemic effect is attributable to the known action of GLP-1 to inhibit gastric emptying and to inhibit glucagon secretion. Studies of the effects of GLP-1 agonists (GLP-1 and exendin-4) given together with established insulin doses before a meal supported the hypothesis. The more prolonged actions of exendin-4 were accompanied by greater and more prolonged reduction of glycaemic effects of ingestion of meals in volunteers with CP-negative Type 1 diabetes mellitus, during intensive insulin therapy, in whom delay of gastric emptying was confirmed by studies of blood levels of acetaminophen ingested with the meals. Side effect-free doses of exendin-4 given together with insulin in volunteers with CP-negative Type 1 diabetes receiving continuing intensive insulin therapy demonstrated the capacity of this combination therapy to normalize blood glucose levels after ingestion of meals that were consistent with the dietary program of the volunteers, without apparent increased risk of hypoglycaemia within a normal between-meals interval. It is suggested that further and more prolonged studies of the use of long-acting GLP-1 agonists as congeners with insulin in Type 1 diabetes mellitus are indicated.
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PMID:Glycaemic effects of incretins in Type 1 diabetes mellitus: a concise review, with emphasis on studies in humans. 1578 Apr 34

beta-Cell transplantation is viewed as a cure for type 1 diabetes; however, it is limited by the number of pancreas donors. Human stem cells offer the promise of an abundant source of insulin-producing cells, given the existence of methods for manipulating their differentiation. We have previously demonstrated that the expression of the beta-cell transcription factor pancreatic duodenal homeobox 1 (PDX-1) in human fetal liver cells activates multiple aspects of the beta-cell phenotype. These cells, termed FH-B-TPN cells, produce insulin, release insulin in response to physiological glucose levels, and replace beta-cell function in diabetic immunodeficient mice. However, they deviate from the normal beta-cell phenotype by the lack of expression of a number of beta-cell genes, the expression of non-beta-cell genes, and a lower insulin content. Here we aimed to promote differentiation of FH-B-TPN cells toward the beta-cell phenotype using soluble factors. Cells cultured with activin A in serum-free medium upregulated expression of NeuroD and Nkx2.2 and downregulated paired box homeotic gene 6 (PAX-6). Glucokinase and prohormone convertase 1/3 were also upregulated, whereas pancreatic polypeptide and glucagon as well as liver markers were downregulated. Insulin content was increased by up to 33-fold, to approximately 60% of the insulin content of normal beta-cells. The cells were shown to contain human C-peptide and release insulin in response to physiological glucose levels. Cell transplantation into immunodeficient diabetic mice resulted in the restoration of stable euglycemia. The cells continued to express insulin in vivo, and no cell replication was detected. Thus, the manipulation of culture conditions induced a significant and stable differentiation of FH-B-TPN cells toward the beta-cell phenotype, making them excellent candidates for beta-cell replacement in type 1 diabetes.
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PMID:Differentiation of human liver-derived, insulin-producing cells toward the beta-cell phenotype. 1612 44

Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.
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PMID:Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes. 1624 46

This study addresses the characterization of human islet-like structures generated from a newly discovered sparse population of precursor cells (Petropavlovskaia and Rosenberg, 2002) in the human pancreas. These cells may be progenitor cells capable of producing pancreatic cells suitable for the treatment of type 1 diabetes. The cells were cultured successfully in non-adherent stationary cultures and yielded, as an important first step, a 1.9-fold expansion in a serum-free medium developed specifically for this cell type. This expanded population grew as pancreatic cell aggregates, which were analyzed for islet-like characteristics. Specifically, through RT-PCR analyses and functionality assays, we show that cells within the population expressed all four of the endocrine hormone genes and proteins (insulin, glucagon, somatostatin, pancreatic polypeptide). As well, the expanded pancreatic precursor cell population exhibited glucose responsiveness although the produced cells appeared to be still primitive in nature.
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PMID:Characterization of human islet-like structures generated from pancreatic precursor cells in culture. 1634

We recently found that pancreatic acinar cells isolated from normal adult mouse can transdifferentiate into insulin-secreting cells in vitro. Using two different animal models of type 1 diabetes, we show here that insulin-secreting cells can also be generated from pancreatic acinar cells of rodents in the diabetic state with absolute insulin deficiency. When pancreatic acinar cells of streptozotocin-treated mice were cultured in suspension in the presence of epidermal growth factor and nicotinamide under low-serum condition, expressions of insulin genes gradually increased. In addition, expressions of other pancreatic hormones, including glucagon, somatostatin, and pancreatic polypeptide, were also induced. Analysis by the Cre/loxP-based direct cell lineage tracing system revealed that these newly made cells originated from amylase-expressing pancreatic acinar cells. Insulin secretion from the newly made cells was significantly stimulated by high glucose and other secretagogues. In addition, insulin-secreting cells were generated from pancreatic acinar cells of Komeda diabetes-prone rats, another animal model of type 1 diabetes. The present study demonstrates that insulin-secreting cells can be generated by transdifferentiation from pancreatic acinar cells of rodents in the diabetic state and further suggests that pancreatic acinar cells represent a potential source of autologous transplantable insulin-secreting cells for treatment of type 1 diabetes.
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PMID:Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes. 1692 84

Extract: Diabetes affects over 18 million people in the United States. Approximately one million have type 1 diabetes mellitus (T1D), previously known as juvenile onset diabetes, with the rest of patients having the type 2 diabetes, previously known as adult onset diabetes. Of these two forms of diabetes, T1D is considered more severe since, if left untreated, it is more rapidly fatal than type 2. Furthermore, achieving blood glucose control in patients with T1D tends to be more difficult. Clinician scientists recognized shortly after the 1921 discovery of insulin that it was a miraculous advance in the treatment of diabetes, but it still fell far short of a cure. Therapy for diabetes has since made major strides but substantial difficulties remain for those afflicted, and a cure is still being sought. Current data strongly suggests that T1D is caused by an attack by the immune system on the the pancreatic beta-cells, the cells that physiologically regulate insulin secretion. These beta-cells are located within cell clusters of the pancreas known as the Islets of Langerhans (or simply "islets"). The islets are essentially mini-organs; they are cell clusters composed of an array of endocrine cell types which variously secrete insulin (to lower the blood sugar, along with other effects), glucagon (a hormone released that raises blood sugar levels), somatostatin (a neuropeptide), pancreatic polypeptide, and the recently described hormone resistin. Before insulin was first used therapeutically in 1922, T1D was uniformly fatal.
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PMID:Islet transplantation and the challenges of treating type 1 diabetes. 2070 22


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