Bjoern A. Menge

Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration

OBJECTIVE—β-Cell regeneration has been proposed as a possible treatment for diabetes, but the capacity for new β-cell formation in humans is yet unclear. In young rats, partial pancreatectomy prompts new β-cell formation to restore β-cell mass. We addressed the following questions: In adult humans: 1) Does partial pancreatectomy provoke new β-cell formation and increased β-cell mass? 2) Is β-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 β-cell area of the pancreas remained unchanged (P = 0.11). β-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 ∼50% reduced to 35.6 ± 2.6 ccm3 by the partial pancreatectomy. The total pancreatic volume was unchanged after an interval of 247 ± 160 days (35.4 ± 2.7 ccm3; P = 0.51). CONCLUSIONS—Unlike in rodents, a 50% pancreatectomy does not prompt β-cell regeneration in adult humans. This explains the high incidence of diabetes after pancreatic resections. Such differences in β-cell turnover between rodents and humans should be born in mind when evaluating new treatment options aiming to restore β-cell mass in patients with diabetes.

Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial.

OBJECTIVE This mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized insulin glargine with/without metformin in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a multicenter, randomized, open-label, three-arm trial comparing lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma glucose curve for 4 h after a standardized solid breakfast (AUC PPG0030–0430 h). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA1c, fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed. RESULTS In total, 142 patients were randomized and treated. Lixisenatide 20 µg achieved greater reductions of AUC PPG0030−0430 h compared with liraglutide (marginal mean [95% one-sided CI] treatment difference, −6.0 [−7.8] h ⋅ mmol/L [−108.3 (−140.0) h ⋅ mg/dL] vs. liraglutide 1.2 mg and −4.6 [−6.3] h ⋅ mmol/L [−83.0 (−114.2) h ⋅ mg/dL] vs. liraglutide 1.8 mg; P < 0.001 for both), and gastric emptying was delayed to a greater extent than with liraglutide 1.2 and 1.8 mg (P < 0.001 for treatment comparisons). FPG was unchanged in all treatment arms. At week 8, mean ± SD HbA1c was 6.2 ± 0.4% (44 ± 5 mmol/mol), 6.1 ± 0.3% (44 ± 4 mmol/mol), and 6.1 ± 0.3% (44 ± 4 mmol/mol) for lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean ± SE 24-h heart rate from baseline by 9 ± 1 bpm vs. 3 ± 1 bpm with lixisenatide (P < 0.001). Occurrence of symptomatic hypoglycemia was higher with lixisenatide; gastrointestinal AEs were more common with liraglutide. Lipase levels were significantly increased from baseline with liraglutide 1.2 and 1.8 mg (marginal mean ± SE increase 21 ± 7 IU/L for both; P < 0.05). CONCLUSIONS Lixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles.

Functional Assessment of Pancreatic β-Cell Area in Humans

OBJECTIVE β-Cell mass declines progressively during the course of diabetes, and various antidiabetic treatment regimens have been suggested to modulate β-cell mass. However, imaging methods allowing the monitoring of changes in β-cell mass in vivo have not yet become available. We address whether pancreatic β-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 β-cell area of the pancreas. RESULTS β-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). β-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) β-cell function was unrelated to β-cell area. CONCLUSIONS Glucose control is closely related to pancreatic β-cell area in humans. A C-peptide–to–glucose ratio after oral glucose ingestion appears to better predict β-cell area than fasting measures, such as the HOMA index.

Selective amino acid deficiency in patients with impaired glucose tolerance and type 2 diabetes

INTRODUCTION Amino acids are important modulators of glucose metabolism, insulin secretion and insulin sensitivity. However, little is known about the changes in amino acid metabolism in patients with diabetes. PATIENTS AND METHODS The circulating amino acid levels were determined in 17 patients with type 2 diabetes, 17 individuals with impaired glucose tolerance (IGT), and 14 control subjects. RESULTS Total amino acid concentrations were 2850+/-57micromol/l in patients with type 2 diabetes, 2980+/-77micromol/l in individuals with IGT, and 2886+/-74micromol/l in control subjects (p=0.38). Patients with type 2 diabetes exhibited significant reductions in the concentrations of gamma-aminobutyric acid (GABA), arginine, glutamine and phosphoethanolamine (p<0.05), whereas valine levels were higher than in controls (p=0.008). In IGT subjects, GABA levels were reduced, while tyrosine concentrations were increased (p<0.05). The plasma levels of essential amino acids were positively related to fasting and post-challenge glucose levels, fasting C-peptide, HOMA insulin resistance and fasting glucagon levels (p<0.05). CONCLUSIONS Total amino acid levels are similar in patients with diabetes, IGT subjects and controls, but the individual levels of several amino acids differ significantly between these groups. These alterations may contribute to the disturbances in insulin secretion and action in diabetic patients and may provide a rationale for offering specific amino acid supplementations to diabetic patients.

Reduced Pancreatic Volume and β-Cell Area in Patients With Chronic Pancreatitis

BACKGROUND & AIMS Chronic pancreatitis (CP) often leads to the development of diabetes. To understand better this pathogenic mechanism, we investigated whether islet cell area and pancreatic volume are reduced in CP patients, islet cell turnover increases in CP patients, and islet cells are less vulnerable to apoptosis than acinar cells. METHODS Pancreatic tissues from 43 patients with CP and 27 controls were examined by immunohistochemistry and quantitative morphometry. Pancreas volume was determined using abdominal computed tomography data. RESULTS The pancreatic volumes were 64.9 +/- 4.3 cm(3) in CP patients and 82.3 +/- 6.7 cm(3) in controls (P = .035). beta-cell areas were 0.69% +/- 0.08% in CP patients and 0.97% +/- 0.08% in controls (P = .017), whereas alpha-cell areas did not differ between the groups (P = .47). There were no differences in the frequencies of replication among groups of alpha-cells, beta-cells, duct cells, or acinar cells nor were there differences in numbers of apoptotic alpha-cells or beta-cells between CP patients and controls. However, CP patients had an approximately 10-fold increase in numbers of apoptotic acinar cells compared with controls (P < .0001). CONCLUSIONS Pancreatic volume was reduced by 21%, and the area comprising beta-cells was reduced by 29% in patients with CP. The lack of increased beta-cells turnover in CP patients, despite an approximately 10-fold increase in the number of apoptotic acinar cells, suggests that the damage to the pancreas is highly specific for the exocrine compartment and affects the endocrine islets to a lesser extent.

Hyperglycemia Acutely Lowers the Postprandial Excursions of Glucagon-Like Peptide-1 and Gastric Inhibitory Polypeptide in Humans

INTRODUCTION Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes. It is unclear whether this is a primary defect or a consequence of the hyperglycemia in type 2 diabetes. We examined whether acute hyperglycemia reduces the postprandial excursions of gastric inhibitory polypeptide (GIP) and GLP-1, and if so, whether this can be attributed to changes in gastric emptying. PATIENTS AND METHODS Fifteen nondiabetic individuals participated in a euglycemic clamp and a hyperglycemic clamp experiment, carried out over 285 min. A mixed meal was ingested after 45 min. Plasma concentrations of glucose, insulin, C-peptide, glucagon, triglycerides, GIP, and GLP-1 were determined, and gastric emptying was assessed using a (13)C-octanoate breath test. RESULTS Glucose levels were 160 +/- 1 mg/dl during the hyperglycemic clamp experiments and 83 +/- 3 mg/dl during the euglycemia (P < 0.0001). Glucose infusion rates were higher during hyperglycemia, but meal ingestion led to a decline in glucose requirements in both experiments (P < 0.0001). Insulin and C-peptide levels were higher during the hyperglycemic clamp experiments (P < 0.0001), whereas glucagon levels were higher during euglycemia (P < 0.0001). The postprandial increases in GIP and GLP-1 concentrations were 46 and 52% lower during the experiments with hyperglycemia (P = 0.0017 and P = 0.021). Hyperglycemia also elicited a significant delay in gastric emptying (P < 0.0001). CONCLUSIONS Hyperglycemia acutely reduces the postprandial levels of GIP and GLP-1, possibly through a deceleration of gastric emptying. This supports the concept that reduced incretin levels in some patients with type 2 diabetes are a consequence rather than a cause of type 2 diabetes.

Amino acid malnutrition in patients with chronic pancreatitis and pancreatic carcinoma.

Objectives: Chronic pancreatitis (CP) and pancreatic cancer (CA) have been associated with intestinal malabsorption and inflammation. However, little is known about the changes in amino acid metabolism in such patients. Methods: The circulating amino acid levels were determined in 12 patients with CP, 12 CA patients, and 12 controls. Results: Total amino acid concentrations were 2850 ± 71 &mgr;mol/L in controls, 2640 ± 96 &mgr;mol/L in CP patients, and 2210 ± 123 &mgr;mol/L in CA patients (P < 0.001). In CP patients, significant reductions in the concentrations of citrulline, &ggr;-aminobutyric acid, taurine, and aspartic acid were found (P < 0.05), whereas in CA patients, the levels of phosphoethanolamine, &ggr;-aminobutyric acid, aspartic acid, taurine, arginine, threonine, alanine, citrulline, and tryptophan were reduced. There was a significant inverse relationship between the total amino acid levels and the white blood cell counts (r = −0.44, P = 0.008). Conclusions: Both patients with CP and with CA exhibit alterations in amino acid levels. The mechanisms underlying these defects may involve intestinal malabsorption as well as systemic inflammation. Providing selective amino acid supplementation to such patients may minimize the excess morbidity and mortality associated with protein malnutrition.

Impaired Glucose-Induced Glucagon Suppression after Partial Pancreatectomy

INTRODUCTION The glucose-induced decline in glucagon levels is often lost in patients with type 2 diabetes. It is unclear whether this is due to an independent defect in alpha-cell function or secondary to the impairment in insulin secretion. We examined whether a partial pancreatectomy in humans would also impair postchallenge glucagon concentrations and, if so, whether this could be attributed to the reduction in insulin levels. PATIENTS AND METHODS Thirty-six patients with pancreatic tumours or chronic pancreatitis were studied before and after approximately 50% pancreatectomy with a 240-min oral glucose challenge, and the plasma concentrations of glucose, insulin, C-peptide, and glucagon were determined. RESULTS Fasting and postchallenge insulin and C-peptide levels were significantly lower after partial pancreatectomy (P < 0.0001). Likewise, fasting glucagon concentrations tended to be lower after the intervention (P = 0.11). Oral glucose ingestion elicited a decline in glucagon concentrations before surgery (P < 0.0001), but this was lost after partial pancreatectomy (P < 0.01 vs. preoperative values). The loss of glucose-induced glucagon suppression was found after both pancreatic head (P < 0.001) and tail (P < 0.05) resection. The glucose-induced changes in glucagon levels were closely correlated to the respective increments in insulin and C-peptide concentrations (P < 0.01). CONCLUSIONS The glucose-induced suppression in glucagon levels is lost after a 50% partial pancreatectomy in humans. This suggests that impaired alpha-cell function in patients with type 2 diabetes may also be secondary to reduced beta-cell mass. Alterations in glucagon regulation should be considered as a potential side effect of partial pancreatectomies.

Long-term recovery of β-cell function after partial pancreatectomy in humans.

Glucose homeostasis is significantly altered immediately after partial pancreatectomy. The present study examined the long-term consequences of a hemipancreatectomy in 10 patients with chronic pancreatitis and 10 patients with benign pancreatic and extrapancreatic tumors. A 240-minute oral glucose challenge was performed before and shortly after pancreatic surgery, as well as after a follow-up of 3.1 ± 0.5 years. Plasma concentrations of glucose, insulin, and C-peptide were determined; and indices of insulin sensitivity and insulin secretion were calculated. In both groups of patients, fasting and postchallenge glucose concentrations were significantly altered immediately after surgery, but returned to preoperative levels at the time of follow-up (P < .0001). Postchallenge insulin and C-peptide concentrations were reduced immediately after surgery (P < .0001), but were partly normalized at the time of follow-up (P < .0001). These changes were not accompanied by improvements in insulin sensitivity (Matsuda index). However, the oral disposition index revealed a significant recovery of β-cell function at the time of follow-up (P < .05). These findings demonstrate a capacity for recovery of glucose control after partial pancreatectomy and suggest that β-cell function can improve significantly over time even in adult humans.

Proinsulin levels in patients with pancreatic diabetes are associated with functional changes in insulin secretion rather than pancreatic β-cell area

INTRODUCTION Hyperproinsulinaemia has been reported in patients with type 2 diabetes. It is unclear whether this is due to an intrinsic defect in β-cell function or secondary to the increased demand on the β-cells. We investigated whether hyperproinsulinaemia is also present in patients with secondary diabetes, and whether proinsulin levels are associated with impaired β-cell area or function. PATIENTS AND METHODS Thirty-three patients with and without diabetes secondary to pancreatic diseases were studied prior to pancreatic surgery. Intact and total proinsulin levels were compared with the pancreatic β-cell area and measures of insulin secretion and action. RESULTS Fasting concentrations of total and intact proinsulin were similar in patients with normal, impaired (including two cases of impaired fasting glucose) and diabetic glucose tolerance (P=0.58 and P=0.98 respectively). There were no differences in the total proinsulin/insulin or intact proinsulin/insulin ratio between the groups (P=0.23 and P=0.71 respectively). There was a weak inverse association between the total proinsulin/insulin ratio and pancreatic β-cell area (r(2)=0.14, P=0.032), whereas the intact proinsulin/insulin ratio and the intact and total proinsulin levels were unrelated to β-cell area. However, a strong inverse relationship between homeostasis model assessment index of β-cell function and both the total and the intact proinsulin/insulin ratio was found (r(2)=0.55 and r(2)=0.48 respectively). The association of insulin resistance (IR) with intact proinsulin was much weaker than the correlation with fasting insulin. CONCLUSIONS Hyperproinsulinaemia is associated with defects in insulin secretion rather than a reduction in β-cell area. The weak association between intact proinsulin and IR argues against the usefulness of this parameter in clinical practice.