Correlations of In Vivo β-Cell Function Tests With β-Cell Mass and Pancreatic Insulin Content in Streptozocin-Administered Baboons

McCulloch, David K.; Koerker, Donna J.; Kahn, Steven E.; Bonner-Weir, Susan; Palmer, Jerry P.

doi:10.2337/diab.40.6.673

Cited by 105 publications

(51 citation statements)

References 42 publications

(71 reference statements)

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“…Alternatively, it is possible that either AIR or PI (or both) may reflect the overall health or volume of the pancreatic ␤-cell mass. It has been demonstrated that AIR glucose correlates strongly and significantly with directly measured ␤-cell mass and pancreatic insulin content (r ϭ 0.63, P Ͻ 0.02; r ϭ 0.92, P Ͻ 0.001; respectively) in baboons that had received varying doses of streptozocin (47). In addition, a reduced ␤-cell mass could conceivably result in elevated PI concentration, in that the rate of secretion by remaining cells is increased, thereby decreasing the intracellular stores and forcing the release of incompletely processed materials (43).…”

Section: Discussionmentioning

confidence: 99%

Increased Proinsulin Levels and Decreased Acute Insulin Response Independently Predict the Incidence of Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study

et al. 2002

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Previous studies have indicated that ␤-cell dysfunction predicts the development of diabetes, although it is unknown whether the use of combinations of insulin secretory measures further improves prediction. The Insulin Resistance Atherosclerosis Study is a prospective, multicenter, epidemiological study of the relationship between insulin sensitivity and the risk of diabetes and cardiovascular disease. At baseline, fasting concentrations of insulin, intact proinsulin (PI), and split PI were measured, and acute insulin response (AIR) was determined during a frequently sampled intravenous glucose tolerance test (FSIGTT). Subjects who were nondiabetic at baseline (n ‫؍‬ 903) were reexamined after 5 years of follow-up; 148 had developed diabetes. In separate logistic regression models adjusted for age, sex, clinic, and ethnicity, 1 SD differences in measures of ␤-cell dysfunction were associated with diabetes incidence (AIR: odds ratio [OR] 0.37, 95% CI 0.27-0.52; intact PI: OR 1.90, 95% CI 1.57-2.30; split PI: OR 1.94, 95% CI 1.63-2.31). After additional adjustment for BMI, impaired glucose tolerance, and insulin sensitivity, these measures continued to be significantly associated with risk of diabetes (all P < 0.0001). Furthermore, in models that included both PI and AIR, each was an independent predictor, and individuals who had combined low AIR and high PI experienced the highest diabetes risk. In conclusion, both low AIR and high PI independently predicted diabetes in a well-characterized multiethnic population. Although fasting PI is simpler to assess, determining AIR from an FSIGTT may further improve prediction. If pharmacological agents to prevent diabetes are proved to be efficacious in ongoing clinical trials, then it may be beneficial to perform FSIGTTs to identify better (for intensive intervention) prediabetic subjects who would ultimately require lifelong pharmacological therapy.

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Section: Discussionmentioning

confidence: 99%

Increased Proinsulin Levels and Decreased Acute Insulin Response Independently Predict the Incidence of Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study

et al. 2002

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“…A question that arises from the present study is: what is the significance of an ϳ60% decrease in ␤-cell mass in humans? Although rodents tolerate a partial pancreatectomy in which up to 80% of the ␤-cell mass is removed (28), primates (29) and pigs (30) develop diabetes with a decrease of ␤-cell mass of ϳ50% or greater. Furthermore, humans who have had ϳ50% of their pancreas removed have abnormal glucose tolerance (some developing diabetes by more recent classification) and diminished insulin secretion in response to a hyperglycemic clamp (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes

et al. 2003

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Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in ␤-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m 2 ; 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m 2 ; 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative ␤-cell volume, frequency of ␤-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative ␤-cell volume was increased in obese versus lean nondiabetic cases (P ‫؍‬ 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative ␤-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of ␤-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of ␤-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that ␤-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased ␤-cell apoptosis. Since the major defect leading to a decrease in ␤-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and ␤-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia. Diabetes 52:102-110, 2003

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“…Our results are also consistent with the previous finding by other investigators [35] who observed that insulin-treated Type II diabetic subjects contained lower beta-cell volume (mean: 0.41 ml) than subjects treated with oral compounds (0.52 ml) and diet (0.8 ml). Massive loss of beta cells such as that observed in a 95 %-partial pancreatectomy in rodents [36] or a 50 % reduction of beta-cell mass in streptozotocin-injected baboons [37] is required to induce hyperglycaemia. It is not therefore likely that the reduction of beta-cell mass found in our study could, by itself, account for the onset of diabetes.…”

Section: Discussionmentioning

confidence: 99%

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

et al. 2002

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Impaired insulin secretion and insulin resistance are a characteristic feature of Type II (non-insulin-dependent) diabetes mellitus [1,2]. In spite of extensive studies on the pathophysiology of diabetes, islet pathology and its pathogenesis remain controversial.Classical studies using histochemical methods to identify endocrine cells have reported varying results, including the severe loss of beta cells [3], modest changes with amyloid deposition [4,5] and even no change of islet beta-cell population [6]. Immunohistochemical techniques for the identification of specific populations of islet endocrine cells, showed a nearly 50 % reduction in beta-cell volume density in European Type II non-obese diabetic patients compared with non-diabetic control subjects [7]. Other studies have reported a 24 % reduction of islet beta-cell area density, a 58 % increase in A cell area density and a deposition of amyloid that correlated with the severity of islet pathology [8]. In another study of European Type II diabetic patients, a separate research group has reported Diabetologia (2002) Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients Abstract Aims/hypothesis. We examined the pancreatic islet lesions in Japanese patients with Type II diabetes mellitus to determine if the damage was related to oxidative stress. Methods. Morphometric analyses were performed on immunostained sections of the tail portion of the pancreas from 14 diabetic and 15 non-diabetic patients. Amyloid deposition and oxidative stress-induced tissue damage were evaluated by Congo-red staining and immunostaining. Resistance to oxidative stress was assessed from immunostaining results for Cu, Zn-superoxide dismutase (SOD). Expression of (pro)insulin mRNA was assessed by in situ hybridisation. Results. The pancreas from diabetic patients had amyloid deposition in about 15 % of the islets, intensified reactions of 8-OHdG and HNE, as well as reduced expression of SOD. Islet volume density of beta cells and total beta-cell mass in the pancreas from diabetic patients were reduced by 22 % (p < 0.001) and 30 % (p < 0.05). Islet volume density and total mass of (pro)insulin mRNA-positive cells were similarly reduced in diabetic patients by 22 % (p < 0.001) and 39 % (p < 0.05), respectively. Islet volume density of A cells was increased by 20 % (p < 0.001) but total mass did not change. There were no changes in volume densities of islet, D and PP cells. Reduced beta-cell volume density correlated with increased positive staining of 8-OHdG. Conclusion/interpretation. Japanese Type II diabetic patients show a reduction of beta-cell mass and evidence of increased oxidative stress-related tissue damage that is correlated with the extent of the beta-cell lesions. [Diabetologia (2002) 45: 85±96]

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Correlations of In Vivo β-Cell Function Tests With β-Cell Mass and Pancreatic Insulin Content in Streptozocin-Administered Baboons

Cited by 105 publications

References 42 publications

Increased Proinsulin Levels and Decreased Acute Insulin Response Independently Predict the Incidence of Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study

Increased Proinsulin Levels and Decreased Acute Insulin Response Independently Predict the Incidence of Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study

β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

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