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Robert A. Ritzel

Bio: Robert A. Ritzel is an academic researcher from University of California, Los Angeles. The author has contributed to research in topics: Insulin & Diabetes mellitus. The author has an hindex of 10, co-authored 11 publications receiving 4210 citations. Previous affiliations of Robert A. Ritzel include Heidelberg University & University of Southern California.

Papers
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Journal ArticleDOI
01 Jan 2003-Diabetes
TL;DR: Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation andβ-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 Diabetes.
Abstract: Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-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 beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-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 beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-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 beta-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 beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-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.

3,710 citations

Journal ArticleDOI
TL;DR: There was a significant relationship between the -cell volume and fasting blood glucose concentration, with a point of inflection at x 1.1%.
Abstract: 36.5 5.3 kg/m 2 ). We only included people with type 2 diabetes who were not taking insulin or glucose-lowering oral medications, both of which would have influenced the measured blood glucose concentrations and the relationship of these with -cell volume. The relationship between fractional -cell volume and fasting blood glucose concentration was analyzed by nonlinear regression analysis to establish the best monoexponential fit of the relationship between the fasting blood glucose (dependent variable) and the -cell volume (independent variable); y span exp(k X) plateau and the point of inflection of the hyperbole. ANOVA was used to test for the effect of -cell volume on fasting blood glucose. RESULTS— There was a significant relationship between the -cell volume and fasting blood glucose concentration, with a point of inflection at x 1.1 0.1%. This relationship is curvilinear (Fig. 1) so that -cell deficiency beyond 1.1% is associated with a steep increase in blood glucose with each further decrement in -cell mass.

194 citations

Journal ArticleDOI
01 Jan 2007-Diabetes
TL;DR: A novel hypothesis for impaired insulin secretion in type 2 diabetes and following islet transplantation is proposed, specifically disrupted cell-to-cell adherence in islets through the actions of membrane-disrupting IAPP oligomers.
Abstract: Insulin secretion from the 2,000-3,000 beta-cells in an islet is a highly synchronized activity with discharge of insulin in coordinate secretory bursts at approximately 4-min intervals. Insulin secretion progressively declines in type 2 diabetes and following islet transplantation. Both are characterized by the presence of islet amyloid derived from islet amyloid polypeptide (IAPP). In the present studies, we examined the action of extracellular human IAPP (h-IAPP) on morphology and function of human islets. Because oligomers of h-IAPP are known to cause membrane disruption, we questioned if application of h-IAPP oligomers to human islets would lead to disruption of islet architecture (specifically cell-to-cell adherence) and a decrease in coordinate function (e.g., increased entropy of insulin secretion and diminished coordinate secretory bursts). Both hypotheses are affirmed, leading to a novel hypothesis for impaired insulin secretion in type 2 diabetes and following islet transplantation, specifically disrupted cell-to-cell adherence in islets through the actions of membrane-disrupting IAPP oligomers.

181 citations

Journal ArticleDOI
01 Jul 2003-Diabetes
TL;DR: It is postulate that beta-cell deficiency in type 2 diabetes may result in part from failure to adaptively increase beta- cell mass due to increased vulnerability of replicating beta-cells to undergo apoptosis, and if this postulate is correct, inhibition of apoptosis should allow recovery of Beta-cell mass in type 1 diabetes.
Abstract: Type 2 diabetes is characterized by a relative beta-cell deficit as a result of increased beta-cell apoptosis and islet amyloid derived from the beta-cell peptide islet amyloid polypeptide (IAPP). Human IAPP (h-IAPP) but not mouse IAPP (m-IAPP) induces apoptosis when applied to cells in culture, a property that depends on the propensity of h-IAPP to oligomerize. Since beta-cell mass is regulated, the question arises as to why it is not adaptively increased in response to insulin resistance and hyperglycemia in type 2 diabetes. This adaptation might fail if dividing beta-cells preferentially underwent apoptosis. We tested the hypothesis that beta-cells are preferentially vulnerable to h-IAPP-induced apoptosis. We established a microculture environment to perform time-lapse video microscopy (TLVM) and studied beta-cells (RIN) and HeLa cells undergoing replication or apoptosis. Sequential images (every 10 min for 36 h in RIN or 24 h in HeLa cells) of cells in vivo were analyzed, and each mitotic and apoptotic event was documented. Freshly dissolved h-IAPP caused a dose-dependent increased rate of apoptosis (P < 0.0001) in both cell types. At low and medium levels of toxicity, cells that had previously undergone mitosis were more vulnerable to h-IAPP-induced apoptosis than nondividing cells (P < 0.05). In the first 3 h after mitosis (full cell cycle length 26 +/- 0.6 h), beta-cells were particularly susceptible to h-IAPP-induced apoptosis (P < 0.05). Neither m-IAPP nor mature amyloid aggregates of h-IAPP were cytotoxic (P = 0.49). To corroborate these cell culture studies, we examined sections of human pancreatic tissue (five cases of type 2 diabetes) and human islets incubated for 48 h +/- h-IAPP. Both were stained for apoptosis with the transferase-mediated dUTP nick-end labeling method and analyzed for the presence of paired apoptotic cells anticipated in the event of postmitotic apoptosis. In human pancreatic tissue 26 +/- 5% (single plane of examination) and in human islets incubated with h-IAPP 44 +/- 4% of apoptotic islet cells were paired. In conclusion, replicating beta-cells are preferentially vulnerable to h-IAPP-induced apoptosis in cell culture. Postmitotic apoptosis was also documented in humans with type 2 diabetes and in human islet tissue. We postulate that beta-cell deficiency in type 2 diabetes may result in part from failure to adaptively increase beta-cell mass due to increased vulnerability of replicating beta-cells to undergo apoptosis. If this postulate is correct, then inhibition of apoptosis should allow recovery of beta-cell mass in type 2 diabetes.

118 citations

Journal ArticleDOI
TL;DR: Whether chronic elevated glucose concentrations induce both defects involved in impaired insulin secretion in TTDM: deficiency and decreased orderliness of insulin secretion is addressed.
Abstract: In health, most insulin is secreted in pulses. Type 2 diabetes mellitus (TTDM) is characterized by impaired pulsatile insulin secretion with a defect in insulin pulse mass. It has been suggested that this defect is partly due to chronic overstimulation of beta-cells imposed by insulin resistance and hyperglycemia, which results in depletion of pancreatic insulin stores. It has been reported that in TTDM overnight inhibition of insulin secretion (induction of beta-cell rest) leads to quantitative normalization of pulsatile insulin secretion upon subsequent stimulation. Recently, decreased orderliness of insulin secretion has been recognized as another attribute of impaired insulin secretion in TTDM. In the current studies we sought to address at the level of the isolated islet whether chronic elevated glucose concentrations induce both defects involved in impaired insulin secretion in TTDM: deficiency and decreased orderliness of insulin secretion. We use the concept of beta-cell rest, induced by a novel beta-cell selective K(ATP)-channel opener (KCO), NN414 (6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide), to test whether preservation of insulin stores leads to normalization of both processes in response to glucose stimulation. Human islets were isolated from three cadaveric organ donors and studied in perifusion experiments and static incubation. Acute activation of K(ATP)-channels suppressed insulin secretion from perifused human islets by approximately 90% (P < 0.0001). This KCO also inhibited glucagon secretion in a dose-dependent manner (P = 0.01). Static incubation at 11 and 16 vs. 4 mM glucose for 96 h decreased islet insulin stores by approximately 80% and 85% (P < 0.0001, respectively). In subsequent perifusion experiments, total insulin secretion ( approximately 30%; P < 0.01) from these islets and insulin pulse mass ( approximately 40%; P < 0.05) were both decreased (11 vs. 4 mM). The inhibition of insulin secretion during static incubation with KCO reduced the loss of islet insulin stores in a dose-dependent manner (P < 0.0001) and resulted in increased total insulin secretion (2.6-fold; P < 0.01) and insulin pulse mass (2.5-fold; P < 0.05) during subsequent perifusion. The orderliness of insulin secretion was significantly reduced after chronic incubation of human islets at 11 mM glucose (P = 0.04), but induction of beta-cell rest at 11 mM failed to normalize the regularity of insulin secretion during subsequent perifusion. We conclude that physiological increased glucose concentrations (11 mM), which are frequently observed in diabetes, lead to a loss of islet insulin stores and defective pulsatile insulin secretion as well as reduced orderliness of insulin secretion. Induction of beta-cell rest by selective activation of beta-cell K(ATP)-channels preserves insulin stores and pulsatile insulin secretion without restoring the orderliness of insulin secretion. Therefore, the concept of beta-cell rest may provide a strategy to protect beta-cells from chronic overstimulation and to improve islet function. Impaired glucose-regulated insulin secretion in TTDM may, however, partially involve mechanisms that are distinct from insulin stores and insulin secretion rates.

76 citations


Cited by
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Journal ArticleDOI
14 Dec 2006-Nature
TL;DR: In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance.
Abstract: Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention

4,515 citations

Journal ArticleDOI
TL;DR: Clinical trials with the incretin mimetic exenatide and liraglutide show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) associated with weight loss, but long-term clinical studies are needed to determine the benefits of targeting the inc retin axis for the treatment of type 2 diabetes.

3,497 citations

Journal ArticleDOI
TL;DR: The main actions of GLP-1 are to stimulate insulin secretion and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions and acts as an enterogastrone and part of the "ileal brake" mechanism.
Abstract: Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

2,657 citations

Journal ArticleDOI
01 Apr 2009-Diabetes
TL;DR: Eight players comprise the ominous octet and dictate that treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects.
Abstract: Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function. The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

2,184 citations

Journal ArticleDOI
TL;DR: It is postulate that this variability in the severity of insulin resistance varies greatly among obese people might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acid.
Abstract: Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.

1,980 citations