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Open Access Publications from the University of California

Scholarly Works (51 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2016)
    Cover page: Glucagon-Like Peptide 1 Drugs as Second-Line Therapy for Type 2 Diabetes
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2014)
    The insulin-degrading enzyme (IDE) has been identified as a type 2 diabetes and Alzheimer's disease susceptibility gene, though its physiological function remains unclear. Maianti et al. (2014) now propose that an IDE inhibitor may be a promising therapeutic strategy for type 2 diabetes.
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2015)
      Type 2 diabetes (T2D) is a highly prevalent and chronic metabolic disorder. Recent evidence suggests that formation of toxic aggregates of the islet amyloid polypeptide (IAPP) might contribute to β-cell dysfunction and disease. However, the mechanism of protein aggregation and associated toxicity remains unclear. Misfolding, aggregation, and accumulation of diverse proteins in various organs is the hallmark of the group of protein misfolding disorders (PMDs), including highly prevalent illnesses affecting the central nervous system (CNS) such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this review we discuss the current understanding of the mechanisms implicated in the formation of protein aggregates in the endocrine pancreas and associated toxicity in the light of the long-standing knowledge from neurodegenerative disorders associated with protein misfolding.
        Cover page: Type 2 diabetes as a protein misfolding disease
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2017)

        Context

        Pancreatic duct glands (PDGs) have been proposed as a source of regeneration in response to exocrine pancreas injury, and thus may serve as an organ stem cell niche. There is evidence to suggest ongoing β-cell formation in longstanding type 1 diabetes (T1D), but the source is unknown.

        Objective

        To investigate the PDG compartment of the pancreas in humans with T1D for evidence of an active regenerative signature (presence of progenitor cells and increased proliferation) and, in particular, as a potential source of β-cells.

        Design, setting, and participants

        Pancreases from 46 brain dead organ donors (22 with T1D, 24 nondiabetic controls) were investigated for activation (increased proliferation) and markers of pancreatic exocrine and endocrine progenitors.

        Results

        PDG cell replication was increased in T1D (6.3% ± 1.6% vs 0.6% ± 0.1%, P < 0.001, T1D vs nondiabetic), most prominently in association with pancreatic inflammation. There were increased progenitor-like cells in PDGs of T1D, but predominantly with an exocrine fate.

        Conclusion

        The PDG compartment is activated in T1D consistent with a response to ongoing inflammation, and via resulting ductal hyperplasia may contribute to local obstructive pancreatitis and eventual pancreatic atrophy characteristic of T1D. However, there is no evidence of effective endocrine cell formation from PDGs.
          Cover page: Increased Proliferation of the Pancreatic Duct Gland Compartment in Type 1 Diabetes.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2005)

          In health, insulin is secreted in discrete pulses into the portal vein, and the regulation of the rate of insulin secretion is accomplished by modulation of insulin pulse mass. Several lines of evidence suggest that the pattern of insulin delivery by the pancreas determines hepatic insulin clearance. In previous large animal studies, the amplitude of insulin pulses was related to the extent of insulin clearance. In humans (and in large animals), the amplitude of insulin oscillations is 100-fold higher in the portal vein than in the systemic circulation, despite only a fivefold dilution, implying preferential hepatic extraction of insulin pulses. In the present study, by direct hepatic vein sampling in healthy humans, we sought to establish the extent of first-pass hepatic insulin extraction and to determine whether the pattern of insulin secretion (insulin pulse mass and amplitude) dictates the hepatic insulin clearance and thereby delivery of insulin to extrahepatic insulin-responsive tissues. Five nondiabetic subjects (two men and three women, mean age 32 years [range 25-39], BMI 24.9 kg/m(2) [21.2-27.1]) participated. Insulin and C-peptide delivery from the splanchnic bed was measured in basal overnight-fasted state and during a glucose infusion of 2 mg kg(-1) min(-1) by simultaneous sampling from the hepatic vein and an arterialized vein along with direct estimation of splanchnic blood flow. Fractional insulin extraction was calculated from the difference between the C-peptide and insulin delivery rates from the liver. The time patterns of insulin concentrations and hepatic insulin clearance were analyzed by deconvolution and Cluster analysis, respectively. Cross-correlation analysis was used to relate C-peptide secretion and insulin clearance. Glucose infusion increased peripheral glucose concentrations from 5.4 0.1 to 6.4 0.4 mmol/l (P < 0.05). Likewise, insulin and C-peptide concentrations increased during glucose infusion (P < 0.05). Hepatic insulin clearance increased with glucose infusion (1.06 0.18 vs. 2.55 0.38 pmol kg(-1) min(-1); P < 0.01), but fractional hepatic insulin clearance was stable (78.2 4.4 vs. 84 0. 3.9% , respectively; P = 0.18). Insulin secretory-burst mass rose during glucose infusion (P < 0.05), whereas the interburst interval remained unchanged (4.4 0.2 vs. 4.5 0.3 min; P = 0.36). Cluster analysis identified an oscillatory pattern in insulin clearance, with peaks occurring approximately every 5 min. Cross-correlation analysis between prehepatic C-peptide secretion and hepatic insulin clearance demonstrated a significant positive association without detectable (< 1 min) time lag. Insulin secretory-burst mass strongly predicted insulin clearance (r = 0.81, P = 0.0043). In conclusion, in humans, 80% of insulin is extracted during the first liver passage. The liver rapidly responds to fluctuations in insulin secretion, preferentially extracting insulin delivered in pulses. The mass (and therefore amplitude) of insulin pulses traversing the liver is the predominant determinant of hepatic insulin clearance. Therefore, through this means, the pulse mass of insulin release dictates both hepatic (directly) as well as extra-hepatic (indirectly) insulin delivery. These findings emphasize the dual role of the liver and pancreas and their relationship mediated through magnitude of insulin pulse mass in regulating the quantity and pattern of systemic isulin delivery.

            Cover page: Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2013)
              Cover page: Response to Comment on: Saisho et al. β-Cell Mass and Turnover in Humans: Effects of Obesity and Aging. Diabetes Care 2013;36:111–117
              • Article
              • Peer Reviewed
              Dermatology Online Journal, Volume 8, Issue 2 (2002)
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2017)

                Aims/hypothesis

                We sought to establish whether the increased incidence of diabetes associated with Down syndrome was due to a congenital deficit in β cells.

                Methods

                The pancreas was obtained at autopsy from nondiabetic subjects with Down syndrome (n = 29) and age-matched nondiabetic control subjects without Down syndrome (n = 28). The pancreas sections were evaluated for the fractional β-cell area.

                Results

                No difference was found in the fractional β-cell area between the subjects with Down syndrome and the control subjects.

                Conclusions/interpretations

                The increased incidence and prevalence of diabetes in individuals with Down syndrome is not due to an underlying congenital deficiency of β cells.
                  Cover page: Down Syndrome-Associated Diabetes Is Not Due To a Congenital Deficiency in β Cells
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2016)
                  Immunohistochemistry (IHC) and immunofluorescence (IF) staining techniques are important diagnostic tools of anatomic pathology in the clinical setting and widely used analytical tools in research laboratories. In diabetes research, they are routinely used for the assessment of beta- and alpha-cell mass, for assessment of endocrine cell distribution within the pancreas, for evaluation of islet composition and islet morphology. Here, we present the evaluation of IHC techniques for the detection of alpha-cells in human pancreatic tissue. We compared the Horse Radish Peroxidase (HRP)-based method utilizing DAB Peroxidase Substrate to the Alkaline Phosphatase (AP)-based method utilizing Vector Red substrate. We conclude that HRP-DAB staining is a robust and reliable method for detection of alpha-cells using either rabbit polyclonal or mouse monoclonal anti-glucagon antibodies. However, AP-Vector Red staining should be used with caution, because it is affected by the dehydration with ethanol and toluene preceding the mounting of slides with Permount mounting medium. When AP-Vector Red is a preferable method for alpha-cell labeling, slides should be mounted using aqueous mounting medium or, alternatively, they could be air-dried before permanent mounting.
                    Cover page: Evaluation of immunohistochemical staining for glucagon in human pancreatic tissue.
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2013)
                    There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk.
                      Cover page: A Critical Analysis of the Clinical Use of Incretin-Based Therapies
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