Mechanisms of Impaired Fasting Glucose and Glucose Intolerance Induced by a ∼50% Pancreatectomy

Abstract

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) often coexist and as such represent a potent risk factor for subsequent development of type 2 diabetes. ␤-Cell mass is ϳ50% deficient in IFG and ϳ65% deficient in type 2 diabetes. To establish the effect of a ϳ50% deficit in ␤-cell mass on carbohydrate metabolism, we performed a ϳ50% partial pancreatectomy versus sham surgery in 14 dogs. Insulin secretion was quantified from insulin concentrations measured in the portal vein at 1-min sampling intervals under basal conditions, after a 30-g oral glucose, and during a hyperglycemic clamp. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp combined with isotope dilution. Partial pancreatectomy resulted in IFG and IGT. After partial pancreatectomy both basal and glucose-stimulated insulin secretion were decreased through the mechanism of a selective ϳ50 and ϳ80% deficit in insulin pulse mass, respectively (P < 0.05). These defects in insulin secretion were partially offset by decreased hepatic insulin clearance (P < 0.05). Partial pancreatectomy also caused a ϳ40% decrease in insulinstimulated glucose disposal (P < 0.05), insulin sensitivity after partial pancreatectomy being related to insulin pulse amplitude (r ‫؍‬ 0.9, P < 0.01). We conclude that a ϳ50% deficit in ␤-cell mass can recapitulate the alterations in glucose-mediated insulin secretion and insulin action in humans with IFG and IGT. These data support a mechanistic role of a deficit in ␤-cell mass in the evolution of IFG/IGT and subsequently type 2 diabetes. Diabetes 55: [2347][2348][2349][2350][2351][2352][2353][2354][2355][2356] 2006 T ype 2 diabetes is characterized by insulin resistance and impaired glucose-mediated insulin secretion (1,2). Although the basis for the defective insulin secretion remains unknown, a contributory factor may be the ϳ65% deficit in ␤-cell mass (3,4). Interestingly, a relatively high proportion of living related donors who underwent a ϳ50% pancreatectomy subsequently developed diabetes (5). Also, humans with impaired fasting glucose (IFG) have a ϳ50% deficit in ␤-cell mass (3), implying that a deficit in ␤-cell mass may be important in the pathophysiology of type 2 diabetes.Further support for this hypothesis is provided by the observation that pharmacological or surgical reduction of ␤-cell mass in rats (6,7), pigs (8), dogs (9 -12), or monkeys (13) results in defective insulin secretion and, depending on the extent of the induced deficit in ␤-cell mass, diabetes or IFG. The purpose of the current study was to reproduce in dogs the ϳ50% deficit in ␤-cell mass present in humans with IFG in order to address the following questions. First, does a 50% deficit in ␤-cell mass lead to IFG and/or impaired glucose tolerance (IGT)? Second, does a ϳ50% deficit in ␤-cell mass lead to impaired glucose-stimulated insulin secretion, and, if so, does this reproduce the pattern seen in humans with type 2 diabetes? Third, does a 50% deficit in ␤-cell mass lead to a change in insulin sensitivity, and, ...

Metabolic consequences of a 50% partial pancreatectomy in humans

“…diabetes has been observed after a loss of approximately 50% of beta cells [5,6]. Consistent with these animal data, recent studies using pancreas samples from human autopsies have provided evidence that glucose levels begin to rise when the extent of beta cells has been reduced by approximately 50% [7]; the extent of beta cell loss in patients with overt diabetes is reported to be approximately 65% [1].…”

“…Indeed, any reduction in beta cell mass and insulin secretion would be expected to result in a worsening of post-challenge glucose control [3,5,8]. Therefore, the question arises what mechanisms were responsible for the reduction in glycaemic excursions observed in these patients; two possibilities come to mind.…”

“…The metabolic consequences arising from such selective beta cell loss are multifaceted and comprise an impairment in glucose-induced insulin secretion and, in particular, a diminished insulin pulse mass, as well as an impairment in peripheral insulin action [5,6,8]. However, while a number of previous studies have examined the metabolic changes arising from an experimental reduction of beta cell mass in animal models [5,6,8,9], little is known about the effects of an approximately 50% partial pancreatectomy in humans [10].…”

“…However, while a number of previous studies have examined the metabolic changes arising from an experimental reduction of beta cell mass in animal models [5,6,8,9], little is known about the effects of an approximately 50% partial pancreatectomy in humans [10]. This question is particularly relevant because the capacity for islet regeneration after partial pancreatectomy differs substantially between different species [4,[11][12][13], thereby potentially leading to marked differences in the insulin secretory capacity following such surgical intervention.…”

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

“…Experimental reduction of beta cell mass in rodents and dogs by partial pancreatectomy (Px) severe enough to cause hyperglycaemia results in defective glucose-stimulated insulin secretion (GSIS) and peripheral insulin resistance [8][9][10]. In animals with less radical reduction in beta cell mass, an additional metabolic insult such as high sucrose diet [7] or corticosteroids [11] is necessary to cause hyperglycaemia.…”