The objective of this research is to gain a greater understanding of the cause of fasting and postprandial hyperglycemia in people with type 2 diabetes. Endogenous glucose production is excessive ...before eating and fails to appropriately suppress after eating in people with type 2 diabetes. This is due in part to impaired insulin-induced suppression of endogenous glucose production, which is observed early in the evolution of type 2 diabetes. Increased rates of gluconeogenesis and perhaps glycogenolysis contribute to hepatic insulin resistance. Insulin-induced stimulation of hepatic glucose uptake and hepatic glycogen synthesis are reduced in people with type 2 diabetes primarily due to decreased uptake of extracellular glucose presumably because of inadequate activation of hepatic glucokinase. Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present. The premise of these studies, as well as those performed by many other investigators, is that an understanding of the pathogenesis of type 2 diabetes will enable the development of targeted therapies that are directed toward correcting specific metabolic defects in a given individual. I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia. While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future.
A simulation model of the glucose-insulin system in the postprandial state can be useful in several circumstances, including testing of glucose sensors, insulin infusion algorithms and decision ...support systems for diabetes. Here, we present a new simulation model in normal humans that describes the physiological events that occur after a meal, by employing the quantitative knowledge that has become available in recent years. Model parameters were set to fit the mean data of a large normal subject database that underwent a triple tracer meal protocol which provided quasi-model-independent estimates of major glucose and insulin fluxes, e.g., meal rate of appearance, endogenous glucose production, utilization of glucose, insulin secretion. By decomposing the system into subsystems, we have developed parametric models of each subsystem by using a forcing function strategy. Model results are shown in describing both a single meal and normal daily life (breakfast, lunch, dinner) in normal. The same strategy is also applied on a smaller database for extending the model to type 2 diabetes.
Fasting hyperglycemia occurs when an excessive rate of endogenous glucose production (EGP) is not accompanied by an adequate compensatory increase in the rate of glucose disappearance (Rd). The ...situation following food ingestion is more complex as the amount of glucose that reaches the circulation for disposal is a function of the systemic rate of appearance of the ingested glucose (referred to as the rate of meal appearance Rameal), the pattern and degree of suppression of EGP, and the rapidity of stimulation of the Rd In an effort to measure these processes, Steele et al. proposed what has come to be referred to as the dual-tracer method in which the ingested glucose is labeled with one tracer while a second tracer is infused intravenously at a constant rate. Unfortunately, subsequent studies have shown that although this approach is technically simple, the marked changes in plasma specific activity or the tracer-to-tracee ratio, if stable tracers are used, introduce a substantial error in the calculation of Rameal, EGP, and Rd, thereby leading to incorrect and at times misleading results. This Perspective discusses the causes of these so-called "nonsteady-state" errors and how they can be avoided by the use of the triple-tracer approach.
We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age.
We examined human autopsy pancreas from 167 nondiabetic individuals ...20-102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects.
β-Cell mass is increased by ~50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age.
β-Cell mass in human obesity increases by ~50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.
Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by ...denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1, and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism.
Aims/hypothesis
Shift-work is associated with circadian rhythm disruption and an increased risk of obesity and type 2 diabetes. We sought to determine the effect of rotational shift-work on glucose ...metabolism in humans.
Methods
We studied 12 otherwise healthy nurses performing rotational shift-work using a randomised crossover study design. On each occasion, participants underwent an isotope-labelled mixed meal test during a simulated day shift and a simulated night shift, enabling simultaneous measurement of glucose flux and beta cell function using the oral minimal model. We sought to determine differences in fasting and postprandial glucose metabolism during the day shift vs the night shift.
Results
Postprandial glycaemic excursion was higher during the night shift (381±33 vs 580±48 mmol/l per 5 h,
p
<0.01). The time to peak insulin and C-peptide and nadir glucagon suppression in response to meal ingestion was also delayed during the night shift. While insulin action did not differ between study days, the beta cell responsivity to glucose (59±5 vs 44±4 × 10
−9
min
−1
;
p
<0.001) and disposition index were decreased during the night shift.
Conclusions/interpretation
Impaired beta cell function during the night shift may result from normal circadian variation, the effect of rotational shift-work or a combination of both. As a consequence, higher postprandial glucose concentrations are observed during the night shift.
β-Cell Replication Is the Primary Mechanism Subserving the Postnatal Expansion of β-Cell Mass in Humans
Juris J. Meier 1 ,
Alexandra E. Butler 1 ,
Yoshifumi Saisho 1 ,
Travis Monchamp 2 ,
Ryan ...Galasso 1 ,
Anil Bhushan 1 ,
Robert A. Rizza 3 and
Peter C. Butler 1
1 Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, Los Angeles, California
2 Division of Endocrinology, Diabetes and Hypertension, UCLA David Geffen School of Medicine, Los Angeles, California
3 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota
Corresponding author: Peter C. Butler, Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 24-130
Warren Hall, 900 Veteran Ave., Los Angeles, CA 90095-7073. E-mail: pbutler{at}mednet.ucla.edu
Abstract
OBJECTIVE— Little is known about the capacity, mechanisms, or timing of growth in β-cell mass in humans. We sought to establish if the
predominant expansion of β-cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively
abundant β-cell replication. We also sought to establish if there is a secondary growth in β-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 ) β-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 β-cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary
accelerated growth phase during adolescence, 4 ) β-cell mass (and presumably growth) is highly variable between individuals, and 5 ) a high rate of β-cell replication is coincident with the major postnatal expansion of β-cell mass.
CONCLUSIONS— These data imply that regulation of β-cell replication during infancy plays a major role in β-cell mass in adult humans.
CT, computed tomography
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 11 March 2008. DOI: 10.2337/db07-1369.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 26, 2008.
Received September 26, 2007.
DIABETES
Evaluation of the existence of a diurnal pattern of glucose tolerance after mixed meals is important to inform a closed-loop system of treatment for insulin requiring diabetes. We studied 20 healthy ...volunteers with normal fasting glucose (4.8 ± 0.1 mmol/L) and HbA(1c) (5.2 ± 0.0%) to determine such a pattern in nondiabetic individuals. Identical mixed meals were ingested during breakfast, lunch, or dinner at 0700, 1300, and 1900 h in randomized Latin square order on 3 consecutive days. Physical activity was the same on all days. Postprandial glucose turnover was measured using the triple tracer technique. Postprandial glucose excursion was significantly lower (P < 0.01) at breakfast than lunch and dinner. β-Cell responsivity to glucose and disposition index was higher (P < 0.01) at breakfast than lunch and dinner. Hepatic insulin extraction was lower (P < 0.01) at breakfast than dinner. Although meal glucose appearance did not differ between meals, suppression of endogenous glucose production tended to be lower (P < 0.01) and insulin sensitivity tended to be higher (P < 0.01) at breakfast than at lunch or dinner. Our results suggest a diurnal pattern to glucose tolerance in healthy humans, and if present in type 1 diabetes, it will need to be incorporated into artificial pancreas systems.
β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes
Alexandra E. Butler 1 ,
Juliette Janson 2 ,
Susan Bonner-Weir 3 ,
Robert Ritzel 1 ,
Robert A. Rizza 4 and
Peter C. Butler ...1
1 Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, Los Angeles, California
2 Karolinska Institute, Stockholm, Sweden
3 Joslin Diabetes Center, Boston, Massachusetts
4 Division of Endocrinology, Mayo Clinic, Rochester, Minnesota
Abstract
Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in β-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 β-cell volume, frequency of β-cell apoptosis and replication,
and new islet formation from exocrine ducts (neogenesis). Relative β-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 β-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of β-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 β-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 β-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased
β-cell apoptosis. Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while
new islet formation and β-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.
Footnotes
Address correspondence and reprint requests to Dr. Peter C. Butler, Division of Endocrinology and Diabetes, Keck School of
Medicine, University of Southern California, 1333 San Pablo St., BMT-B11, Los Angeles, CA 90033. E-mail: pbutler{at}usc.edu .
Received for publication 19 July 2002 and accepted in revised form 9 October 2002.
FPG, fasting plasma glucose; IAPP, islet amyloid polypeptide; IFG, impaired fasting glucose.
DIABETES
The Oral Minimal Model Method COBELLI, Claudio; MAN, Chiara Dalla; TOFFOLO, Gianna ...
Diabetes (New York, N.Y.),
04/2014, Letnik:
63, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The simultaneous assessment of insulin action, secretion, and hepatic extraction is key to understanding postprandial glucose metabolism in nondiabetic and diabetic humans. We review the oral minimal ...method (i.e., models that allow the estimation of insulin sensitivity, β-cell responsivity, and hepatic insulin extraction from a mixed-meal or an oral glucose tolerance test). Both of these oral tests are more physiologic and simpler to administer than those based on an intravenous test (e.g., a glucose clamp or an intravenous glucose tolerance test). The focus of this review is on indices provided by physiological-based models and their validation against the glucose clamp technique. We discuss first the oral minimal model method rationale, data, and protocols. Then we present the three minimal models and the indices they provide. The disposition index paradigm, a widely used β-cell function metric, is revisited in the context of individual versus population modeling. Adding a glucose tracer to the oral dose significantly enhances the assessment of insulin action by segregating insulin sensitivity into its glucose disposal and hepatic components. The oral minimal model method, by quantitatively portraying the complex relationships between the major players of glucose metabolism, is able to provide novel insights regarding the regulation of postprandial metabolism.
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