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Our aims were (1) by computed tomography (CT) to establish a population database for pancreas volume (parenchyma and fat) from birth to age 100 years, (2) in adults, to establish the impact of gender, obesity, and the presence or absence of type-2 diabetes on pancreatic volume (parenchyma and fat), and (3) to confirm the latter histologically from pancreatic tissue obtained at autopsy with a particular emphasis on whether pancreatic fat is increased in type-2 diabetes. We measured pancreas volume in 135 children and 1,886 adults (1,721 nondiabetic and 165 with type-2 diabetes) with no history of pancreas disease who had undergone abdominal CT scan between 2003 and 2006. Pancreas volume was computed from the contour of the pancreas on each CT image. In addition to total pancreas volume, parenchymal volume, fat volume, and fat/parenchyma ratio (F/P ratio) were determined by CT density. We also quantified pancreatic fat in autopsy tissue of 47 adults (24 nondiabetic and 23 with type-2 diabetes). During childhood and adolescence, the volumes of total pancreas, pancreatic parenchyma, and fat increase linearly with age. From age 20-60 years, pancreas volume reaches a plateau (72.4 +/- 25.8 cm(3) total; 44.5 +/- 16.5 cm(3) parenchyma) and then declines thereafter. In adults, total ( approximately 32%), parenchymal ( approximately 13%), and fat ( approximately 68%) volumes increase with obesity. Pancreatic fat content also increases with aging but is not further increased in type-2 diabetes. We provide lifelong population data for total pancreatic, parenchymal, and fat volumes in humans. Although pancreatic fat increases with aging and obesity, it is not increased in type-2 diabetes.

BACKGROUND: Recent biochemical diagnostic guidelines for insulinomas require demonstration of hypoglycemia with inappropriately elevated (nonsuppressed) insulin, C-peptide, or proinsulin, but these criteria may overlap with those in patients without insulinomas. Use of an 'amended' insulin-glucose ratio that accounts for the normal variation in insulin secretion according to prevailing glycemia may improve diagnostic accuracy. OBJECTIVE: To compare the diagnostic accuracy of current diagnostic guideline criteria with the amended insulin-glucose ratio in patients with a suspected insulinoma. DESIGN: Retrospective cohort study. SETTING: 2 specialized university departments in Germany. PATIENTS: 114 patients with suspected hypoglycemia over 10 years having diagnostic prolonged fasts. MEASUREMENTS: Glucose, insulin, C-peptide, and the amended insulin-glucose ratio were measured during and at discontinuation of prolonged fasts. RESULTS: Of 114 patients who were evaluated, 49 had surgical resection of histologically confirmed insulinomas. Insulinoma was excluded in 65 patients; follow-up for a mean of 10 years (range, 0 to 16 years) showed no progressively severe hypoglycemic events or diagnoses of insulinoma. Patients with insulinoma had lower glucose levels and higher insulin and C-peptide levels overall than did control patients at the end of prolonged fasts, but there was considerable overlap. The amended insulin-glucose ratio correctly identified 48 of 49 patients with insulinoma and excluded the diagnosis in 64 of 65 control patients, resulting in positive and negative predictive values of 0.98 (95% CI, 0.89 to 1.00) and 0.99 (CI, 0.92 to 1.00), respectively, compared with 0.75 (CI, 0.63 to 0.85) and 0.98 (CI, 0.89 to 1.00), respectively, for glucose, insulin, and C-peptide concentration criteria. LIMITATION: The study had a retrospective design, no proinsulin concentrations were available, and a nonspecific insulin immunoassay (crossreactive with proinsulin) was used. CONCLUSION: The amended insulin-glucose ratio showed improved diagnostic accuracy over established criteria that use glucose, insulin, and C-peptide concentrations. PRIMARY FUNDING SOURCE: None. [ABSTRACT FROM AUTHOR]

In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of β-cell apoptosis. Native GLP-1 is degraded within ~2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient. [ABSTRACT FROM AUTHOR]

Objective: Noninvasive determination of pancreatic beta-cell mass in vivo has been hampered by the lack of suitable beta-cell-specific imaging agents. This report outlines an approach for the development of novel ligands homing selectively to islet cells in vivo.Research Design and Methods: To generate agents specifically binding to pancreatic islets, a phage library was screened for single-chain antibodies (SCAs) on rat islets using two different approaches. 1) The library was injected into rats in vivo, and islets were isolated after a circulation time of 5 min. 2) Pancreatic islets were directly isolated, and the library was panned in the islets in vitro. Subsequently, the identified SCAs were extensively characterized in vitro and in vivo.Results: We report the generation of SCAs that bind highly selective to either beta- or alpha-cells. These SCAs are internalized by target cells, disappear rapidly from the vasculature, and exert no toxicity in vivo. Specific binding to beta- or alpha-cells was detected in cell lines in vitro, in rats in vivo, and in human tissue in situ. Electron microscopy demonstrated binding of SCAs to the endoplasmatic reticulum and the secretory granules. Finally, in a biodistribution study the labeling intensity derived from [(125)I]-labeled SCAs after intravenous administration in rats strongly predicted the beta-cell mass and was inversely related to the glucose excursions during an intraperitoneal glucose tolerance test.Conclusions: Our data provide strong evidence that the presented SCAs are highly specific for pancreatic beta-cells and enable imaging and quantification in vivo. [ABSTRACT FROM AUTHOR]

Objective: beta-Cell mass declines progressively during the course of diabetes, and various antidiabetic treatment regimens have been suggested to modulate beta-cell mass. However, imaging methods allowing the monitoring of changes in beta-cell mass in vivo have not yet become available. We address whether pancreatic beta-cell area can be assessed by functional test of insulin secretion in humans.Research Design and Methods: A total of 33 patients with chronic pancreatitis (n = 17), benign pancreatic adenomas (n = 13), and tumors of the ampulla of Vater (n = 3) at various stages of glucose tolerance were examined with an oral glucose load before undergoing pancreatic surgery. Indexes of insulin secretion were calculated and compared with the fractional beta-cell area of the pancreas.Results: beta-Cell area was related to fasting glucose concentrations in an inverse linear fashion (r = -0.53, P = 0.0014) and to 120-min postchallenge glycemia in an inverse exponential fashion (r = -0.89). beta-Cell area was best predicted by a C-peptide-to-glucose ratio determined 15 min after the glucose drink (r = 0.72, P < 0.0001). However, a fasting C-peptide-to-glucose ratio already yielded a reasonably close correlation (r = 0.63, P < 0.0001). Homeostasis model assessment (HOMA) beta-cell function was unrelated to beta-cell area.Conclusions: Glucose control is closely related to pancreatic beta-cell area in humans. A C-peptide-to-glucose ratio after oral glucose ingestion appears to better predict beta-cell area than fasting measures, such as the HOMA index. [ABSTRACT FROM AUTHOR]

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: beta-Cell regeneration has been proposed as a possible treatment for diabetes, but the capacity for new beta-cell formation in humans is yet unclear. In young rats, partial pancreatectomy prompts new beta-cell formation to restore beta-cell mass. We addressed the following questions: In adult humans: 1) Does partial pancreatectomy provoke new beta-cell formation and increased beta-cell mass? 2) Is beta-cell turnover increased after partial pancreatectomy? Research Design and Methods: Protocol 1: human pancreatic tissue was collected from 13 patients who underwent two consecutive partial pancreas resections, and markers of cell turnover were determined in both tissue samples, respectively. Protocol 2: pancreas volumes were determined from abdominal computer tomography scans, performed in 17 patients on two separate occasions after partial pancreatectomy. Results: Protocol 1: fasting glucose concentrations increased significantly after the 50% pancreatectomy (P = 0.01), but the fractional beta-cell area of the pancreas remained unchanged (P = 0.11). beta-Cell proliferation, the overall replication index (Ki67 staining), and the percentage of duct cells expressing insulin were similar before and after the partial pancreatectomy. The overall frequency of apoptosis (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) was slightly increased following the partial pancreatectomy (P = 0.02). Protocol 2: pancreatic volume was approximately 50% reduced to 35.6 +/- 2.6 ccm(3) by the partial pancreatectomy. The total pancreatic volume was unchanged after an interval of 247 +/- 160 days (35.4 +/- 2.7 ccm(3); P = 0.51). Conclusions: Unlike in rodents, a 50% pancreatectomy does not prompt beta-cell regeneration in adult humans. This explains the high incidence of diabetes after pancreatic resections. Such differences in beta-cell turnover between rodents and humans should be born in mind when evaluating new treatment options aiming to restore beta-cell mass in patients with diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to establish whether hypoglycemia after gastric bypass surgery (GBS) for morbid obesity is due to increased fractional beta-cell area or inappropriately increased insulin secretion. RESEARCH DESIGN AND METHODS: We examined pancreata obtained at partial pancreatectomy from 6 patients with post-GBS hypoglycemia and compared these with 31 pancreata from obese subjects and 16 pancreata from lean control subjects obtained at autopsy. We addressed the following questions. In patients with post-GBS hypoglycemia, is beta-cell area increased and is beta-cell formation increased or beta-cell apoptosis decreased? RESULTS: We report that in patients with post-GBS hypoglycemia, beta-cell area was not increased compared with that in obese or even lean control subjects. Consistent with this finding, there was no evidence of increased beta-cell formation (islet neogenesis and beta-cell replication) or decreased beta-cell loss in patients with post-GBS hypoglycemia. In control subjects, mean beta-cell nuclear diameter correlated with BMI (r(2) = 0.79, P < 0.001). In patients with post-GBS hypoglycemia, beta-cell nuclear diameter was increased (P < 0.001) compared with that for BMI in matched control subjects but was appropriate for BMI before surgery. CONCLUSIONS: We conclude that post-GBS hypoglycemia is not due to increases in beta-cell mass or formation. Rather, postprandial hypoglycemia after GBS is due to a combination of gastric dumping and inappropriately increased insulin secretion, either as a failure to adaptively decrease insulin secretion after GBS or as an acquired phenomenon. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by an approximately 60% loss of beta-cell mass, a marked defect in postprandial insulin secretion, and a failure to suppress postprandial glucagon concentrations. It is possible that postprandial hyperglucagonemia in type 2 diabetes is due to impaired postprandial insulin secretion. To address this, we studied eight adult Goettingen minipigs before and after an approximately 60% reduction in beta-cell mass induced by alloxan. Pigs were studied fasting and after ingestion of a mixed meal. Insulin and glucagon secretion were determined by deconvolution of blood hormone concentrations measured at 1-min intervals. The relationship between insulin and glucagon release was analyzed using cross-correlation and forward versus reverse cross-approximate entropy. We report that glucagon and insulin were secreted in approximately 4-min pulses. Prealloxan, postprandial insulin secretion drove an approximately 20% suppression of glucagon concentrations (P < 0.01), through inhibition of glucagon pulse mass. The alloxan-induced approximately 60% deficit in beta-cell mass lead to an approximately 70% deficit in postprandial insulin secretion and loss of the postprandial insulin-driven suppression of glucagon secretion. We conclude that postprandial hyperglucagonemia in type 2 diabetes is likely due to loss of intraislet postprandial suppression of glucagon secretion by insulin. [ABSTRACT FROM AUTHOR]

Individuals with type 2 diabetes are at high risk of postprandial falls in blood pressure (BP) (i.e., a reduction in systolic BP of ≥20mmHg, termed postprandial hypotension (PPH)), which increases the risk of falls and mortality. This study evaluated the effects of oral metformin on postprandial BP, heart rate (HR), glucagon-like peptide-1 (GLP-1) and gastric emptying (GE) in individuals with type 2 diabetes. We studied 16 subjects (5 female) before and after ingestion of a 75g radiolabeled glucose drink, after both acute (30 min) and subacute (b.i.d for 7 days) administration of metformin (850mg) or placebo, in a double-blind, randomized, crossover design. 24-hour ambulatory BP measurement following standardized meals (breakfast, lunch and dinner) was used to quantify PPH events. The primary outcome was the postprandial fall in systolic BP. We found that acute administration of metformin did not affect BP, HR, plasma insulin or GLP-1 levels, but slowed GE (P<0.001) and reduced the glycemic response to oral glucose (P<0.001). Sub-acute metformin reduced PPH events by 32% (P=0.035), in association with an increase in HR (P=0.029), slowing of GE (P<0.001), augmentation of plasma GLP-1 (P<0.001), and a reduction in plasma glucose (P<0.001) without affecting plasma insulin. Pre-prandial BP was unaffected by metformin. To conclude, in type 2 diabetes oral metformin attenuates the hypotensive response to meals, associated with stimulation of GLP-1 and slowing of GE to reduce PPH., (© 2025 by the American Diabetes Association.)

Aim: To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy., Materials and Methods: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg -1 ·min -1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg -1 ·min -1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM., Results: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆ max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆ max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each)., Conclusions: Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The role of gut-brain axis functioning gains growing attention in research on the pathophysiology of major depressive disorders. Here, especially consequences of altered microbiota composition on tryptophan metabolism resulting in altered serotonergic neurotransmission in the central nervous system (CNS) have reached a central position. Previous research, however, mainly focused on either microbiota and peripheral serotonin levels or central serotonergic neurotransmission. The present study aimed to combine the analysis of microbiota composition and central serotonergic activity using a valid neurophysiological indicator. We recruited 19 adult patients with type 1 diabetes and depression (D + D; 7 males), 19 patients with type 1 diabetes (D-; 7 male), and 20 healthy participants (HC; 7 males). Next to the analysis of fecal microbiota regarding α- and β-diversity, the loudness dependence of auditory evoked potential (LDAEP) was investigated, a non-invasive measurement of central serotonergic activity. High α-diversity was associated with high LDAEP, i.e., low serotonergic activity, in patients with diabetes and additional depression. Furthermore, relative abundances of bacterial families belonging to Bacteroidetes, Proteobacteria and Firmicutes were shown to have an impact on central serotonergic activity. This finding was supported by a tendency indicating an association of central serotonergic activity with the Bacteroidetes-Firmicutes ratio in both patients' groups. Together, this data suggests that the guts' microbiota composition might play an important role in regulating the central serotonergic activity in the brain., (© 2023. The Author(s).)

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials., (© 2023 John Wiley & Sons Ltd.)