Studies of pancreatic alpha cell function in normal and diabetic subjects

Unger, Roger H; Aguilar-Parada, E; Müller, W.; Eisentraut, Anna M.

doi:10.1172/jci106297

Cited by 795 publications

(393 citation statements)

References 22 publications

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“…Most studies of patients with overt type 2 diabetes report elevated plasma glucagon levels compared with nondiabetic controls [15,31]. Thus, our finding of lower, and not of elevated plasma glucagon levels during 24 h profiles in carriers of the T allele genotype may appear somewhat paradoxical.…”

Section: Discussioncontrasting

confidence: 53%

“…TCF7L2 encodes a transcription factor that binds to the promoter of the proglucagon gene, which in turn encodes glucagon, glucagon-like peptide (GLP)-1 and GLP-2 [14]. Inappropriately increased glucagon secretion is a described abnormality in individuals with type 2 diabetes [15]. However, it is unknown whether this abnormality is present in prediabetic patients or whether it may be secondary to the diabetic state as such.…”

Section: Introductionmentioning

confidence: 99%

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The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

et al. 2009

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Aims/hypothesis We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. Methods We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. Results Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p<0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p<0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p=0.03) and GIP (p=0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele Diabetologia (2009) 52:1298-1307 DOI 10.1007/s00125-009-1307-x Electronic supplementary

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Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

et al. 2009

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“…It has also been suggested that the alpha cell is resistant to insulin [35]; however, it is difficult to distinguish between impaired glucose sensing and alpha cell insulin resistance. The glucagon response to the stimulatory effect of arginine is higher in patients with type 2 diabetes than in nondiabetic subjects [36]. However, in view of the concurrent hyperglycaemia, it is difficult to distinguish hyper-responsiveness to arginine from faulty glucose sensing.…”

Section: Abnormalities Of Alpha Cell Function In Diabetesmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

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“…collected from the cannulated portal vein into chilled glass tubes containing EDTA for glucagon [4,5] and without EDTA for insulin and both AutoAnalyzer glucose and Beckman (Model ERA-2001) glucose oxidase glucose determinations. During the time periods when the pancreas was perfused with 80 rag/100 ml glucose, the oxygenated perfusate was pumped from a reservoir kept at 38 ~ C. When cr t, or mutarotated glucose was infused, a second perfusate with a high concentration (3000 mg/ 100 ml) of the particular glucose form was introduced with a Harvard pump into the channel containing the oxygenated, warm perfusate with no glucose.…”

Section: Discussionmentioning

confidence: 99%

The effect of glucose anomers upon insulin and glucagon secretion

et al. 1974

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Summary. The precise mechanism of insulin release is unknown, though the presence of a beta cell surface receptor has been postulated. As D-glucose exists in at least two anomerie forms, ct and fl, these were employed to study insulin release in three animal models. After rapid dissolution, each anomer was rapidly injected into intact rats, dogs, and a rat pancreatic perfusion system. There was a trend toward greater insulin secretion and greater suppression of glucagon by the ~. anomer.Key words: glucose anomers, insulin release, glucagon, mutarotation.D-glucose is known to exist in the crystalline state in either the ~ or fl anomerie form. After placing either of the anomers in aqueous solution there is a transformation into an equilibrium state in which 64% is in the fl form and 36% is in the ~ form. Glucose has been shown to be a major stimulant to insulin release, although the exact mechanism is unknown. Current theories include either a direct interaction of glucose upon a receptor site on the beta cell, or a glucose metabolite which causes insulin secretion, or both. To study the effect of these two D-glucose anomers on insulin release, three different animal models were used. This preliminary survey suggests that there may be some difference between the effect of the two forms upon insulin and glucagon secretion. Materials and Methods Acute cr or fl Glucose Administration to RatsMale Charles River Strain albino rats weighing 180--200 g were fasted for 24 h prior to experimentation. They were anesthetized with intraperitoneal sodium pentobarbital (0.1 rag/100 g body weight). A midline abdominal incision was made. Surrounding tissues were dispaced laterally and the aorta and vena cave were separated. A small 3" tubing (Minicath PRlkLDeseret Cat #5084) was placed into the vena cave 3 cm below the renal vein. A stock glucose solution was prepared in sterile normal saline twelve hours prior to use to assure complete mutarotation (64% fl, 36% ~). Alpha and Beta glucose (Sigma Chemical G-5250, Beta, lot #052e-0810 analyzed as 99.2% fl and 0.8% g, and Sigma Chemical G-5000, Alpha, lot #091C-1690 analyzed as 97.6 % ~. and 2.4% fl) were each dissolved by vigorous shaking for 10 sec in sterile * Supported by U.S.P.H.S. grants AM-09748 and AM-15191 and the Joslin Diabetes Foundation, Inc. saline just prior to injection. These glucose solutions were infused over 5 sec in a volume of 1 ml at a concentration of 200 mg/ml and blood was withdrawn and flushed through the tubing three times to assure completeness of the infusion. A volume of 1 ml blood was removed at time 0, and after the infusion at 1, 3, 5 and 10 rain for glucose ~nd insulin determinations [1, 2]. Acute :r and fl Glucose Administration to DogsMongrel dogs weighing between 22 and 26 kg were employed. Twenty-four hours prior to the studies the animals were anesthetized with sodium pentobarbital (10 mg/kg) and catheters were placed into both jugular veins. The tubings were kept patent with a heparin solution (3 units/1 ml of saline). One catheter was used f...

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Studies of pancreatic alpha cell function in normal and diabetic subjects

Cited by 795 publications

References 22 publications

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

Alpha cell function in health and disease: influence of glucagon-like peptide-1

The effect of glucose anomers upon insulin and glucagon secretion

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