Reduction of Glycemic Potentiation: Sensitive Indicator of β-Cell Loss in Partially Pancreatectomized Dogs

Ward, W. Kenneth; Wallum, B. J.; Beard, James C.; Taborsky, Gerald J.; Porte, D.

doi:10.2337/diab.37.6.723

Cited by 72 publications

(44 citation statements)

References 15 publications

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“…Moreover, we have assessed in vivo measures ofbeta cell reserve in donors using the technique ofglucose potentiation of arginine-induced insulin secretion. Our observations in humans confirms the experimental evidence in animals (3,11) that partial pancreatectomy leads to a decrease in the functional reserve of the beta cell.…”

Section: Resultssupporting

confidence: 80%

Effects of hemipancreatectomy on pancreatic alpha and beta cell function in healthy human donors.

Seaquist¹,

Robertson²

1992

J. Clin. Invest.

123

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To assess the metabolic consequences of hemipancreatectomy in humans, we determined pancreatic beta and alpha cell function in healthy donors. Donors examined cross-sectionally were found to have significantly decreased glucose-induced phasic insulin secretion and arginine-induced insulin and glucagon secretion as compared to age, sex, and body index-matched controls. However, their fasting glucose and insulin values were not different from controls. Similar observations were found in the prospective evaluation of eight donors before and 15±2 mo after hemipancreatectomy. Beta cell reserve, as measured by glucose potentiation of arginine-induced insulin secretion, was significantly decreased in donors (maximal acute insulin response [AIR..]: donors = 666±84 pM vs controls = 1,772±234 pM) while the PG5, (the glucose value at which the half-maximal response was observed) was the same in the two groups. Donors and controls responded to 60-min continuous intravenous infusions of glucose by reaching identical serum glucose values, despite significantly lower insulin secretory responses in donors. We conclude that hemipancreatectomy in human donors is associated with decreased pancreatic alpha and beta cell function. Since donors generally maintain normoglycemia after hemipancreatectomy despite diminished insulin secretion, our data suggest that healthy humans may compensate for hemipancreatectomy by increasing glucose disposal. (J. Clin. Invest. 1992. 89:1761-1766

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Section: Resultssupporting

confidence: 80%

Effects of hemipancreatectomy on pancreatic alpha and beta cell function in healthy human donors.

Seaquist¹,

Robertson²

1992

J. Clin. Invest.

123

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“…This finding suggests that simple β-cell mass reduction is insufficient to produce β-cell dysfunction or that a greater degree of mass reduction is necessary. The ability of the reduced number of β-cells in this in vitro model to adapt functionally is in keeping with observations of β-cell functional adaptation to decreased mass in rodents [24] and dogs [25].…”

Section: Discussionsupporting

confidence: 58%

Glucose- and time-dependence of islet amyloid formation in vitro

Zraika

Hull

Udayasankar

et al. 2007

Biochemical and Biophysical Research Communications

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Islet amyloid contributes to the loss of β-cell mass in type 2 diabetes. To examine the roles of glucose and time on amyloid formation, we developed a rapid in vitro model using isolated islets from human islet amyloid polypeptide (hIAPP) transgenic mice. Islets from hIAPP transgenic and non-transgenic mice were cultured for up to 7 days with either 5.5, 11.1, 16.7 or 33.3 mmol/l glucose. At various time-points throughout the culture period, islets were harvested for determination of amyloid and β-cell areas, and for measures of cell viability, insulin content and secretion. Following culture of hIAPP transgenic islets in 16.7 or 33.3 mmol/l glucose, amyloid formation was significantly increased compared to 5.5 or 11.1 mmol/l glucose culture. Amyloid was detected as early as day 2 and increased in a time-dependent manner so that by day 7, a decrease in the proportion of β-cell area in hIAPP transgenic islets was evident. When compared to non-transgenic islets after 7-day culture in 16.7 mmol/l glucose, hIAPP transgenic islets were 24% less viable, had decreased β-cell area and insulin content, but displayed no change in insulin secretion. Thus, we have developed a rapid in vitro model of light microscopy-visible islet amyloid formation that is both glucose-and time-dependent. Formation of amyloid in this model is associated with reduced cell viability and β-cell loss but adequate functional adaptation. It thus enables studies investigating the mechanism(s) underlying the amyloid-associated loss of β-cell mass in type 2 diabetes. Keywords islet amyloid; human islet amyloid polypeptide; islets; ß-cell; insulin secretion; cell viability; amylin; mouse model; diabetes Islet amyloid polypeptide (IAPP) is a normal product of the pancreatic β-cell. Human, but not rodent, IAPP is capable of forming amyloid deposits, which are associated with loss of both β-cell mass and normal islet function [1,2]. Models have been developed to elucidate the underlying mechanisms responsible for the deleterious effects of amyloidogenesis. Initially, these involved the extracellular application of human IAPP (hIAPP) to immortalized cells [3], or the transfection of cells that lack the sophisticated secretory machinery that is typical of the β-cell [4]. While cell death and/or impaired insulin secretion were demonstrated, these models do not depict what is occurring in humans.

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“…However, no information is available concerning pulsatile insulin release in these patients. A 64% pancreatectomy in dogs also led to a decrease in insulin secretion in response to arginine that was most pronounced at increased plasma glucose concentrations (i.e., glucose potentiation was decreased) (30). In humans after hemipancreatectomy and dogs after an approximately two-thirds pancreatectomy, both the fasting plasma glucose and the insulin concentrations (measured by conventional immunoassay) were normal, raising the question, "How does a decreased capacity for insulin secretion adapt to prevent the development of diabetes?"…”

Section: Discussionmentioning

confidence: 99%

“…This approach is to be contrasted to measuring insulin clearance by infusing exogenous insulin, which has been shown to be unaffected by a partial pancreatectomy (30). We previously showed that partial suppression of insulin secretion achieved with a low-dose infusion of somatostatin reduces the clearance rate of endogenously secreted insulin (32).…”

Section: Discussionmentioning

confidence: 99%

Decrease in β-Cell Mass Leads to Impaired Pulsatile Insulin Secretion, Reduced Postprandial Hepatic Insulin Clearance, and Relative Hyperglucagonemia in the Minipig

et al. 2001

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Most insulin is secreted in discrete pulses at an interval of ϳ6 min. Increased insulin secretion after meal ingestion is achieved through the mechanism of amplification of the burst mass. Conversely, in type 2 diabetes, insulin secretion is impaired as a consequence of decreased insulin pulse mass. ␤-cell mass is reported to be deficient in type 2 diabetes. We tested the hypothesis that decreased ␤-cell mass leads to decreased insulin pulse mass. Insulin secretion was examined before and after an ϳ60% decrease in ␤-cell mass achieved by a single injection of alloxan in a porcine model. Alloxan injection resulted in stable diabetes (fasting plasma glucose 7.4 ؎ 1.1 vs. 4.4 ؎ 0.1 mmol/l; P < 0.01) with impaired insulin secretion in the fasting and fed states and during a hyperglycemic clamp (decreased by 54, 80, and 90%, respectively). Deconvolution analysis revealed a selective decrease in insulin pulse mass (by 54, 60, and 90%) with no change in pulse frequency. Rhythm analysis revealed no change in the periodicity of regular oscillations after alloxan administration in the fasting state but was unable to detect stable rhythms reliably after enteric or intravenous glucose stimulation. After alloxan administration, insulin secretion and insulin pulse mass (but not insulin pulse interval) decreased in relation to ␤-cell mass. However, the decreased pulse mass (and pulse amplitude delivered to the liver) was associated with a decrease in hepatic insulin clearance, which partially offset the decreased insulin secretion. Despite hyperglycemia, postprandial glucagon concentrations were increased after alloxan administration (103.4 ؎ 6.3 vs. 92.2 ؎ 2.5 pg/ml; P < 0.01). We conclude that an alloxan-induced selective decrease in ␤-cell mass leads to deficient insulin secretion by attenuating insulin pulse mass, and that the latter is associated with decreased hepatic insulin clearance and relative hyperglucagonemia, thereby emulating the pattern of islet dysfunction observed in type 2 diabetes. Diabetes 50: [2001][2002][2003][2004][2005][2006][2007][2008][2009][2010][2011][2012] 2001 T ype 2 diabetes is characterized by impaired glucose-mediated insulin secretion (1,2). This has been documented by demonstrating reduced first-phase insulin release in response to intravenous glucose (3,4) and impaired insulin release after glucose ingestion (1,5) and during a hyperglycemic clamp (6). Further analyses indicate that most insulin secretion is derived from discrete insulin secretory bursts (7,8), the mass of which is diminished in patients with type 2 diabetes (9). In addition, it has been reported that ␤-cell mass may be decreased in patients with type 2 diabetes (10), although this remains controversial. Indeed, the role of any decrease in the ␤-cell mass in the pathogenesis of impaired insulin secretion and the pathogenesis of hyperglycemia in type 2 diabetes remains uncertain.In the present study, we addressed the hypothesis that defective insulin secretion in type 2 diabetes can be recapitulated by a selective decreas...

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Reduction of Glycemic Potentiation: Sensitive Indicator of β-Cell Loss in Partially Pancreatectomized Dogs

Cited by 72 publications

References 15 publications

Effects of hemipancreatectomy on pancreatic alpha and beta cell function in healthy human donors.

Effects of hemipancreatectomy on pancreatic alpha and beta cell function in healthy human donors.

Glucose- and time-dependence of islet amyloid formation in vitro

Decrease in β-Cell Mass Leads to Impaired Pulsatile Insulin Secretion, Reduced Postprandial Hepatic Insulin Clearance, and Relative Hyperglucagonemia in the Minipig

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