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Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an ∼40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P < 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P < 0.01). Pancreata in DM treated with incretin therapy were notable for α-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. β-Cell mass was reduced by ∼60% in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumors.

Objectiveβ-Cell turnover and its potential to permit β-cell regeneration in adult primates are unknown. Our aims were 1) to measure β-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of β-cell replication and formation of new β-cells from other precursors (defined thus as β-cell neogenesis); and 3) to establish whether there is an adaptive increase in β-cell formation (attempted regeneration) in streptozotocin (STZ)-induced diabetes in adult nonhuman primates.Research design and methodsAdult (aged 7 years) vervet monkeys were administered STZ (45-55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. β-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates.Resultsβ-Cell turnover is present in adult nonhuman primates (3.3 ± 0.9 mg/month), mostly (~80%) derived from β-cell neogenesis. β-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, β-cell apoptosis was not increased in monkeys administered STZ.ConclusionsThere is ongoing β-cell turnover in adult nonhuman primates that cannot be accounted for by β-cell replication. There is no evidence of β-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce β-cell apoptosis in nonhuman primates in vivo.

Objectiveβ-Cell turnover and its potential to permit β-cell regeneration in adult primates are unknown. Our aims were 1) to measure β-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of β-cell replication and formation of new β-cells from other precursors (defined thus as β-cell neogenesis); and 3) to establish whether there is an adaptive increase in β-cell formation (attempted regeneration) in streptozotocin (STZ)-induced diabetes in adult nonhuman primates.Research design and methodsAdult (aged 7 years) vervet monkeys were administered STZ (45-55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. β-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates.Resultsβ-Cell turnover is present in adult nonhuman primates (3.3 ± 0.9 mg/month), mostly (~80%) derived from β-cell neogenesis. β-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, β-cell apoptosis was not increased in monkeys administered STZ.ConclusionsThere is ongoing β-cell turnover in adult nonhuman primates that cannot be accounted for by β-cell replication. There is no evidence of β-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce β-cell apoptosis in nonhuman primates in vivo.

ObjectiveThe islet in type 2 diabetes is characterized by β-cell apoptosis, β-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in β-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system.Research design and methodsWe used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.ResultsWe report accumulation of polyubiquinated proteins and UCH-L1 deficiency in β-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in β-cells induced endoplasmic reticulum stress leading to apoptosis.ConclusionsOur results indicate that defective protein degradation in β-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises β-cell viability.

ObjectiveWe sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes.Research design and methodsHIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and beta-cell mass, function, and turnover were measured in each group.ResultsSitagliptin plus metformin had synergistic effects to preserve beta-cell mass in HIP rats. Metformin more than sitagliptin inhibited beta-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. beta-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis.ConclusionsThe combination of metformin and sitagliptin had synergistic actions to preserve beta-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.

ObjectiveObesity is a known risk factor for type 2 diabetes. However, most obese individuals do not develop diabetes because they adapt to insulin resistance by increasing beta-cell mass and insulin secretion. Islet pathology in type 2 diabetes is characterized by beta-cell loss, islet amyloid derived from islet amyloid polypeptide (IAPP), and increased beta-cell apoptosis characterized by endoplasmic reticulum (ER) stress. We hypothesized that IAPP-induced ER stress distinguishes successful versus unsuccessful islet adaptation to insulin resistance.Research design and methodsTo address this, we fed wild-type (WT) and human IAPP transgenic (HIP) rats either 10 weeks of regular chow or a high-fat diet and prospectively examined the relations among beta-cell mass and turnover, beta-cell ER stress, insulin secretion, and insulin sensitivity.ResultsA high-fat diet led to comparable insulin resistance in WT and HIP rats. WT rats compensated with increased insulin secretion and beta-cell mass. In HIP rats, in contrast, neither beta-cell function nor mass compensated for the increased insulin demand, leading to diabetes. The failure to increase beta-cell mass in HIP rats was the result of ER stress-induced beta-cell apoptosis that increased in proportion to diet-induced insulin resistance.ConclusionsIAPP-induced ER stress distinguishes the successful versus unsuccessful islet adaptation to a high-fat diet in rats. These studies are consistent with the hypothesis that IAPP oligomers contribute to increased beta-cell apoptosis and beta-cell failure in humans with type 2 diabetes.

ObjectiveObesity is a known risk factor for type 2 diabetes. However, most obese individuals do not develop diabetes because they adapt to insulin resistance by increasing beta-cell mass and insulin secretion. Islet pathology in type 2 diabetes is characterized by beta-cell loss, islet amyloid derived from islet amyloid polypeptide (IAPP), and increased beta-cell apoptosis characterized by endoplasmic reticulum (ER) stress. We hypothesized that IAPP-induced ER stress distinguishes successful versus unsuccessful islet adaptation to insulin resistance.Research design and methodsTo address this, we fed wild-type (WT) and human IAPP transgenic (HIP) rats either 10 weeks of regular chow or a high-fat diet and prospectively examined the relations among beta-cell mass and turnover, beta-cell ER stress, insulin secretion, and insulin sensitivity.ResultsA high-fat diet led to comparable insulin resistance in WT and HIP rats. WT rats compensated with increased insulin secretion and beta-cell mass. In HIP rats, in contrast, neither beta-cell function nor mass compensated for the increased insulin demand, leading to diabetes. The failure to increase beta-cell mass in HIP rats was the result of ER stress-induced beta-cell apoptosis that increased in proportion to diet-induced insulin resistance.ConclusionsIAPP-induced ER stress distinguishes the successful versus unsuccessful islet adaptation to a high-fat diet in rats. These studies are consistent with the hypothesis that IAPP oligomers contribute to increased beta-cell apoptosis and beta-cell failure in humans with type 2 diabetes.

The islet in type 2 diabetes is characterized by a deficit in beta-cell mass, increased beta-cell apoptosis, and impaired insulin secretion. Also, islets in type 2 diabetes often contain deposits of islet amyloid derived from islet amyloid polypeptide (LAPP), a 37-amino acid protein cosecreted with insulin by beta-cells. Several lines of evidence suggest that proteins with a capacity to develop amyloid fibrils may also form small toxic oligomers that can initiate apoptosis. The amino acid sequence of LAPP in rats and mice is identical and differs from that in humans by substitution of proline residues in the amyloidogenic sequence so that the protein no longer forms amyloid fibrils or is cytotoxic. In the present study, we report a novel rat model for type 2 diabetes: rats transgenic for human LAPP (the HIP rat). HIP rats develop diabetes between 5 and 10 months of age, characterized by an similar to60% deficit in beta-cell mass that is due to an increased frequency of beta-cell apoptosis. HIP rats develop islet amyloid, but the extent of amyloid was not related to the frequency of beta-cell apoptosis (r = 0.10, P = 0.65), whereas the fasting blood glucose was (r = 0.77, P < 0.001). The frequency of beta-cell apoptosis was related to the frequency of beta-cell replication (r = 0.97, P < 0.001) in support of the hypothesis that replicating cells are more vulnerable to apoptosis than nondividing cells. The HIP rat provides additional evidence in support of the potential role of LAPP oligomer formation toward the increased frequency of apoptosis in type 2 diabetes, a process that appears to be compounded by glucose toxicity when hyperglycemia supervenes.

A correction to the article "DNA Methylation-Dependent Restriction of Tyrosine Hydroxylase Contributes to Pancreatic B-Cell Heterogeneity" that was published in a 2023 issue of Diabetes is presented.

Objective: Little is known about the capacity, mechanisms, or timing of growth in beta-cell mass in humans. We sought to establish if the predominant expansion of beta-cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively abundant beta-cell replication. We also sought to establish if there is a secondary growth in beta-cell mass coincident with the accelerated somatic growth in adolescence.Research Design and Methods: To address these questions, pancreas volume was determined from abdominal computer tomographies in 135 children aged 4 weeks to 20 years, and morphometric analyses were performed in human pancreatic tissue obtained at autopsy from 46 children aged 2 weeks to 21 years.Results: We report that 1) beta-cell mass expands by severalfold from birth to adulthood, 2) islets grow in size rather than in number during this transition, 3) the relative rate of beta-cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary accelerated growth phase during adolescence, 4) beta-cell mass (and presumably growth) is highly variable between individuals, and 5) a high rate of beta-cell replication is coincident with the major postnatal expansion of beta-cell mass.Conclusions: These data imply that regulation of beta-cell replication during infancy plays a major role in beta-cell mass in adult humans. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Islets in type 2 diabetes are characterized by a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether LAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice. RESEARCH DESIGN AND METHODS--Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer protein (AβP[sub 1-40]) and anti-oligomer titers, and blood glucose and islet pathology were monitored. RESULTS--Toxic oligomers were detected intracellularly in ∼20-40% of h-IAPP transgenic β-cells. Vaccine induced high titers of anti--h-IAPP toxic oligomers in both transgenic models, but β-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of β-cell mass nor diabetes onset was delayed. CONCLUSIONS--IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP--induced β-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes. Diabetes 56:1324-1332, 2007 [ABSTRACT FROM AUTHOR]

Nondiabetic obese humans adapt to insulin resistance by increasing β-cell mass. In contrast, obese humans with type 2 diabetes have an ∼60% deficit in β-cell mass. Recent studies in rodents reveal that β-cell mass is regulated, increasing in response to insulin resistance through increased β-cell supply (islet neogenesis and β-cell replication) and/or decreased β-cell loss (β-cell apoptosis). Prospective studies of islet turnover are not possible in humans. In an attempt to establish the mechanism for the deficit in β-cell mass in type 2 diabetes, we used an obese versus lean murine transgenic model for human islet amyloid polypeptide (IAPP) that develops islet pathology comparable to that in humans with type 2 diabetes. By 40 weeks of age, obese nontransgenic mice did not develop diabetes and adapted to insulin resistance by a 9-fold increase (P < 0.001) in β-cell mass accomplished by a 1.7-fold increase in islet neogenesis (P < 0.05) and a 5-fold increase in β-cell replication per islet (P < 0.001). Obese transgenic mice developed midlife diabetes with islet amyloid and an 80% (P < 0.001) deficit in β-cell mass that was due to failure to adaptively increase βcell mass. The mechanism subserving this failed expansion was a 10-fold increase in β-cell apoptosis (P < 0.001). There was no relationship between the extent of islet amyloid or the blood glucose concentration and the frequency of β-cell apoptosis. However, the frequency of β-cell apoptosis was related to the rate of increase of islet amyloid. These prospective studies suggest that the formation of islet amyloid rather than the islet amyloid per se is related to increased β-cell apoptosis in this murine model of type 2 diabetes. This finding is consistent with the hypothesis that soluble IAPP oligomers but not islet amyloid are responsible for increased β-cell apoptosis. The current studies also support the concept that replicating β-cells are more vulnerable to apoptosis, possibly accounting for the failure of β-cell mass to expand appropriately in response to obesity in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by a deficit in beta cell mass and insufficient insulin secretion in the setting of increased insulin demand, most commonly as a consequence of obesity. However most obese individuals do not develop type 2 diabetes, with an appropriate adaptive increase in insulin secretion. There is limited data on beta cell mass in well characterized age matched lean versus obese humans. QUESTION. Is beta cell mass adaptively increased in response to obesity in humans? METHODS. We obtained pancreas at autopsy from n= 245 non diabetic humans who were classified as lean (n=108, age 57+25 years, BMI 21.2±2.7), overweight (n=48, age 56±25 years, BMI 27.7±1.3) or obese (n=89, age 60±19 years, BMI 37.4±6.5).Autopsy in all cases was performed within 12 hours of death, pancreas was well preserved and an ambulatory (outpatient) fasting blood glucose value was available within a year prior to death. Fractional beta cell area (fraction of pancreas parenchyma positive for insulin) was measured by morphometric analysis after insulin immunohistochemistry in each pancreas. To obtain population pancreas parenchymal volumes (PV) adjusted for age and BMI we measured PV in 1721 non-diabetic subjects by CT scan. Beta cell mass was then computed in each autopsy case by multiplying the age and BMI adjusted PV appropriate for each autopsy case by the fractional beta cell area (assuming 1 cm³ PV = 1 g). RESULTS. Beta cell mass in adult humans (age range 20 to 59 years) was ∼30% and ∼50% greater in overweight and obese cases compared to lean cases (0.78±0.28g in lean, 0.97±0.42g in overweight and 1.20±0.59g in obese, p<0.05 lean vs. overweight, p<0.0001 lean vs. obese). Beta cell mass correlated with BMI (r=0.4, p<0.0001). CONCLUSIONS. In this large (n=245) cohort of well characterized aged matched non-diabetic humans we report that beta cell mass adaptively increases in response to obesity although modestly (∼50%) in comparison to increased demand for insulin secretion (±300%). These data reveal a modest capacity to increase beta cell mass in adult humans in response to obesity. [ABSTRACT FROM AUTHOR]

Type 1 and 2 diabetes are characterized by ∼90 and 65% deficits in beta-cell mass. Both type 1 and 2 diabetes are reversed by pancreas transplantation but this strategy requires long term immunosuppression and donor pancreases are limited. Therefore exploring the possibility of fostering beta-cell regeneration is an area of active investigation. Strategies to promote tissue regeneration typically employ innate mechanisms of tissue growth. Little is known about the dynamics and mechanisms of postnatal beta-cell growth in humans. QUESTION What are the dynamics and predominant mechanisms of postnatal growth of beta cell mass in humans? METHODS An age adjusted curve for pancreas volume was determined from abdominal computer tomographies of 141 humans aged 4 weeks to 20 years. Morphometric analysis was performed on human pancreatic tissue obtained at autopsy from 46 children aged 2 weeks to 21 years and stained for insulin, TUNEL and Ki67. Beta cell mass was computed by pancreas volume (assuming 1g = cm³) multiplied by fractional beta cell area in each case. Effects of age on pancreas and beta cell mass was evaluated by analysis of quintiles by age. RESULTS Pancreas volume increased in a linear fashion from birth to age 20 yrs (p < 0.000i). The fractional pancreatic area positive for insulin was highest in the youngest age group and decreased with aging (p < 0.05). Beta-cell mass was calculated as 51 mg in the youngest case and increased to 721 ±109 mg in the oldest age group (p < 0.001). While the relative density of islets declined with aging (p < 0.0001), mean islet size increased markedly (p < 0.001), particularly during the first 5 years of age. The percentage of ductal cells positive for insulin was not different between the age groups (p = ns). The frequency of beta-cell replication was highest in the youngest children and declined thereafter. There were no differences in the frequency of beta-cell apoptosis between the age groups, beta cell apoptosis being very rare across all ages. CONCLUSIONS In humans overall pancreas growth is linear from birth to adult life. In contrast, postnatal beta cell growth occurs predominately in the first 5 years after birth, primarily through the mechanism of beta cell replication. The extent of this expansion is several fold but varies considerably between individuals. [ABSTRACT FROM AUTHOR]

Objective: Type 1 and type 2 diabetes are characterized by an approximately 98 and approximately 65% loss of pancreatic beta-cells, respectively. Efforts to reverse either form of diabetes increasingly focus on the possibility of promoting beta-cell replacement and/or regeneration. Islet transplantation has been explored, but it does not provide long-term insulin independence. One possible source of beta-cell regeneration is hematopoietic stem cells. In mice, there are conflicting data as to whether hematopoietic stem cells contribute to pancreatic beta-cells. We sought to establish whether hematopoietic stem cells (derived from adult donors) transdifferentiate into pancreatic beta-cells in adult humans., Research Design and Methods: We addressed this in 31 human pancreata obtained at autopsy from hematopoietic stem cell transplant recipients who had received their transplant from a donor of the opposite sex., Results: Whereas some donor-derived cells were observed in the nonendocrine pancreata, no pancreatic beta-cells were identified that were derived from donor hematopoietic stem cells, including two cases with type 2 diabetes., Conclusions: We conclude that hematopoietic stem cells derived from adult donors contribute minimally to pancreatic beta-cells in nondiabetic adult humans. These data do not rule out the possibility that hematopoietic stem cells contribute to pancreatic beta-cells in childhood or in individuals with type 1 diabetes.

Objective: Islets in type 2 diabetes are characterized by a deficit in beta-cells, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether IAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice., Research Design and Methods: Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer beta protein (AbetaP(1-40)) and anti-oligomer titers, and blood glucose and islet pathology were monitored., Results: Toxic oligomers were detected intracellularly in approximately 20-40% of h-IAPP transgenic beta-cells. Vaccine induced high titers of anti-h-IAPP toxic oligomers in both transgenic models, but beta-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of beta-cell mass nor diabetes onset was delayed., Conclusions: IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP-induced beta-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes.