Accommodation to a reduced islet cell mass in dogs

Marincola, Francesco M.; Cobb, Luther F.; Horaguchi, Atsushi; Maeda, Masaki; Merrell, Ronald C.

doi:10.1152/ajpendo.1984.247.4.e456

Cited by 11 publications

(13 citation statements)

References 11 publications

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“…In a study specifically designed to examine the potential for ␤-cell regeneration, Lö hr et al (25) found a 19% gain in ␤-cell mass 6 weeks after a 60% pancreatectomy in 7-month-old pigs, while an 80% pancreatectomy elicited a 56% increase in ␤-cell mass. Interestingly, when adult dogs were subjected to a similar 80% pancreatectomy, no recovery of insulin secretion or ␤-cell mass was found in the pancreas remnant (26). The most obvious explanation for the discrepancies between these studies is that the capacity for new ␤-cell formation declines with aging.…”

Section: Discussionmentioning

confidence: 99%

Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration

Menge

Tannapfel²,

Belyaev³

et al. 2008

Diabetes

163

108

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OBJECTIVE-␤-Cell regeneration has been proposed as a possible treatment for diabetes, but the capacity for new ␤-cell formation in humans is yet unclear. In young rats, partial pancreatectomy prompts new ␤-cell formation to restore ␤-cell mass. We addressed the following questions: In adult humans: 1) Does partial pancreatectomy provoke new ␤-cell formation and increased ␤-cell mass? 2) Is ␤-cell turnover increased after partial pancreatectomy?RESEARCH DESIGN AND METHODS-Protocol 1: human pancreatic tissue was collected from 13 patients who underwent two consecutive partial pancreas resections, and markers of cell turnover were determined in both tissue samples, respectively. Protocol 2: pancreas volumes were determined from abdominal computer tomography scans, performed in 17 patients on two separate occasions after partial pancreatectomy.RESULTS-Protocol 1: fasting glucose concentrations increased significantly after the 50% pancreatectomy (P ϭ 0.01), but the fractional ␤-cell area of the pancreas remained unchanged (P ϭ 0.11). ␤-Cell proliferation, the overall replication index (Ki67 staining), and the percentage of duct cells expressing insulin were similar before and after the partial pancreatectomy. The overall frequency of apoptosis (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) was slightly increased following the partial pancreatectomy (P ϭ 0.02). Protocol 2: pancreatic volume was ϳ50% reduced to 35.6 Ϯ 2.6 ccm 3 by the partial pancreatectomy. The total pancreatic volume was unchanged after an interval of 247 Ϯ 160 days (35.4 Ϯ 2.7 ccm 3 ; P ϭ 0.51).CONCLUSIONS-Unlike in rodents, a 50% pancreatectomy does not prompt ␤-cell regeneration in adult humans. This explains the high incidence of diabetes after pancreatic resections. Such differences in ␤-cell turnover between rodents and humans should be born in mind when evaluating new treatment options aiming to restore ␤-cell mass in patients with diabetes. Diabetes 57:142-149, 2008 D iabetes develops if ␤-cell mass is diminished below a critical threshold required to sustain adequate insulin secretion at a given level of insulin resistance (1-3). Based on cross-sectional studies (3,4) in human autopsy pancreata, glucose levels start to rise when ␤-cell mass is reduced by more than ϳ50% of normal. Likewise, studies (5,6) in patients with new-onset type 1 diabetes have reported a 50 -70% ␤-cell deficit around the onset of hyperglycemia. The loss of insulin-secreting ␤-cells in both types of diabetes provides a rationale for novel therapeutic approaches aiming to restore ␤-cell mass in diabetic patients.Given the obvious inaccessibility of human pancreas tissue for repeated biopsy sampling in clinical studies, most studies about the dynamics and the mechanisms of ␤-cell regeneration available so far have been carried out in rodent models (7). Among those, the partial pancreatectomy model has been commonly utilized to induce ␤-cell regeneration in mice and rats (8,9). Indeed, following a 90% pancreatectomy in rats, an up to 200% increase ...

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Section: Discussionmentioning

confidence: 99%

Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration

Menge

Tannapfel²,

Belyaev³

et al. 2008

Diabetes

163

108

View full text Add to dashboard Cite

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“…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?" The possibilities were examined by Marincola et al (31) in a study of dogs that had either sham surgery or ϳ80% pancreatectomy. In these studies, pancreatic insulin output was measured directly by sampling from the portal vein.…”

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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“…In contrast, Marincola et al (28) reported that hepatic clearance of insulin may decrease after an 80% pancreatectomy in dogs. Indeed, the values remained remarkably constant after pancreatectomy compared with baseline values.…”

Section: Glucosementioning

confidence: 89%

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

et al. 1988

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To determine which test of islet function is the most sensitive indicator of subclinical beta-cell loss, we studied six conscious dogs before and 1 and 6 wk after removal of the splenic and uncinate lobes [64 +/- 2% pancreatectomy (PX)]. To assess hyperglycemic potentiation, acute insulin secretory responses (AIR) to 5 g i.v. arginine were measured at the fasting plasma glucose (FPG) level after PG was clamped at approximately 250 mg/dl and after PG was clamped at a maximally potentiating level of 550-650 mg/dl. FPG levels were unaffected by PX (112 +/- 4 mg/dl pre-PX vs. 115 +/- 5 mg/dl 6 wk after PX, P NS). Similarly, basal insulin levels remained constant after PX (11 +/- 2 microU/ml pre-PX vs. 11 +/- 1 microU/ml 6 wk after PX, P NS). The AIR to 300 mg/kg i.v. glucose decreased slightly from 42 +/- 9 microU/ml pre-PX to 32 +/- 5 microU/ml 6 wk after PX (P NS), and thus the beta-cell loss was underestimated. In contrast, insulin responses to arginine declined markedly after PX. The AIR to arginine obtained at FPG levels declined from 23 +/- 3 microU/ml pre-PX to 13 +/- 2 microU/ml 6 wk after PX (P = .04). The AIR to arginine obtained at PG levels of approximately 250 mg/dl declined even more, from a pre-PX value of 56 +/- 7 microU/ml to 21 +/- 4 microU/ml 6 wk after PX (P = .02).(ABSTRACT TRUNCATED AT 250 WORDS)

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Accommodation to a reduced islet cell mass in dogs

Cited by 11 publications

References 11 publications

Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration

Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration

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

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

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