Thomas G. K. Breuer

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.

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.

Upper gastrointestinal motility and symptoms in individuals with diabetes, prediabetes and normal glucose tolerance

Aims/hypothesisType 2 diabetes has been associated with upper gastrointestinal motility dysfunction, but the relationship with diabetes duration and glucose control is less well understood. Gastric emptying, oesophageal motility and gastrointestinal symptoms were examined in volunteers with diabetes, prediabetes (impaired fasting glucose [IFG] or impaired glucose tolerance [IGT]) and normal glucose tolerance (NGT).MethodsThe study included 41 patients with type 2 diabetes, 17 individuals with IFG/IGT and 31 individuals with NGT. A gastric emptying breath test and high-resolution oesophageal manometry were performed. Gastrointestinal symptoms were assessed using questionnaires.ResultsGastric emptying was delayed in individuals with IFG/IGT (p < 0.05) but was normal in the diabetic group. Amongst the diabetic patients, gastric emptying rate was fastest in those with longer diabetes duration and the highest HbA1c levels (p < 0.001). Oesophageal motility variables were similar between the groups. However, the lower oesophagus resting pressure was reduced in patients with longer diabetes duration (p = 0.01). Abdominal pain/discomfort was more frequent amongst patients with diabetes (p = 0.04) but was unrelated to gastric emptying. Significant associations between various oesophageal motility variables and gastrointestinal symptoms were observed.Conclusions/interpretationGastric emptying and oesophageal motility are not generally altered in patients with type 2 diabetes. In more advanced disease stages, however, gastric emptying and oesophageal motility may be disturbed, probably as a consequence of autonomic neuropathy. Delayed gastric emptying in IFG/IGT individuals might be secondary to acute hyperglycaemia. Determination of gastric emptying and oesophageal manometry should be considered for the diagnostic workup of patients with diabetes and gastrointestinal symptoms.

Abundance and turnover of GLP-1 producing L-cells in ileal mucosa are not different in patients with and without type 2 diabetes.

INTRODUCTION The gastrointestinal hormone GLP-1 is released from enteroendocrine L-cells and augments postprandial insulin secretion. In patients with type 2 diabetes, the incretin effect is markedly diminished. It is unclear, whether this is due to a reduction in the abundance of L-cells in the intestine. METHODS Ileal tissue samples from 10 patients with and 10 patients without diabetes that underwent surgery for the removal of colon tumors were included. Tissue sections were stained for GLP-1, Ki67, TUNEL and chromogranin A. RESULTS The number of L-cells was not different between patients with and without diabetes in either crypts (1.81±0.21% vs. 1.49±0.24%, respectively; p=0.31) or villi (1.07±0.16% vs. 0.83±0.10%, respectively; p=0.23). L-cell number was higher in crypts than in villi (p<0.0001). L-cell replication was detected rarely and not different between the groups. L-cell apoptosis was similar in patients with and without diabetes in both crypts (7.84±2.77% vs. 8.65±3.77%, p=0.85) and villi (4.48±2.89% vs. 8.62±4.64%, p=0.42). Chromogranin A staining was found in a subset of L-cells only. CONCLUSIONS Intestinal L-cell density is higher in crypts than in villi. Chromogranin A is not a prerequisite for GLP-1 production. L-cell density and turnover are not different between patients with and without diabetes. Thus, alterations in the number of GLP-1 producing cells do not explain the reduced incretin effect in patients with type 2 diabetes.

Defects in α-Cell Function in Patients With Diabetes Due to Chronic Pancreatitis Compared With Patients With Type 2 Diabetes and Healthy Individuals

OBJECTIVE Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose administration in patients with diabetes due to chronic pancreatitis. RESEARCH DESIGN AND METHODS Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypoglycemic clamp and an oral glucose tolerance test (OGTT) were performed. RESULTS Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P < 0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P < 0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P < 0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to β-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis. CONCLUSIONS α-Cell responses to oral glucose ingestion and to hypoglycemia are disturbed in patients with diabetes and chronic pancreatitis and in patients with type 2 diabetes. The similarities between these defects suggest a common etiology.

Impact of proton pump inhibitor treatment on pancreatic beta-cell area and beta-cell proliferation in humans.

INTRODUCTION Gastrin has been shown to promote beta-cell proliferation in rodents, but its effects in adult humans are largely unclear. Proton pump inhibitors (PPIs) lead to endogenous hypergastrinaemia, and improved glucose control during PPI therapy has been reported in patients with diabetes. Therefore, we addressed whether PPI treatment is associated with improved glucose homoeostasis, islet cell hyperplasia or increased new beta-cell formation in humans. PATIENTS AND METHODS Pancreatic tissue specimens from 60 patients with and 33 patients without previous PPI therapy were examined. The group was subdivided into patients without diabetes (n = 27), pre-diabetic patients (n = 31) and patients with diabetes (n = 35). RESULTS Fasting glucose and HbA1c levels were not different between patients with and without PPI therapy (P = 0.34 and P = 0.30 respectively). Beta-cell area was higher in patients without diabetes than in patients with pre-diabetes or diabetes (1.33 ± 0.12%, 1.05 ± 0.09% and 0.66 ± 0.07% respectively; P < 0.0001). There was no difference in beta-cell area between patients with and without PPI treatment (1.05 ± 0.08% vs 0.87 ± 0.08%, respectively; P = 0.16). Beta-cell replication was rare and not different between patients with and without PPI therapy (P = 0.20). PPI treatment was not associated with increased duct-cell replication (P = 0.18), insulin expression in ducts (P = 0.28) or beta-cell size (P = 0.63). CONCLUSIONS These results suggest that in adult humans, chronic PPI treatment does not enhance beta-cell mass or beta-cell function to a relevant extent.

P3: Unexpected high prevalence of hepatitis C in a densly populated metropolitan area of Germany

PURPOSE OF THE STUDY: Recent studies have identified a seroprevalence of hepatitis C of 1.6% in the United States and 0.7% in Germany. A significant variation has, however, been detected between rural and metropolitan areas. Identification of hepatitis C virus (HCV)-positive persons for appropriate counseling and management is the major focus of national prevention programs. Currently, routine testing is recommended for persons most likely to have HCV infection. Our aim was to assess the prevalence of hepatitis C in the German Ruhr region, which is one of the largest and most densely populated metropolitan areas in Europe. METHODS: Between 06/2009 and 07/2010 8435 consecutive patients (46.4% male, 53.6% female) who were admitted to the emergency unit of a tertiary care center (St. Josef Hospital, Ruhr-University Bochum, Germany) were investigated. Tests included analysis of antibodies to HCV (anti-HCV), ASTand ALT-levels and HCV RNA, if applicable. Thirty patients with known replicative hepatitis C infection served as internal control. SUMMARY OF RESULTS: The seroprevalence of anti-HCV was 3.45% (291/8435 patients). 194/291 (66.67%) seropositive individuals were amendable for further evaluation. Viral replication was detected in 70.62% of these patients (137/194) equating to a prevalence of replicative and chronic hepatitis C of 1.62% in this population. Age and sex distribution did not differ between anti-HCV positive patients and negative controls. Following analysis of liver transaminases, significant differences in AST levels between anti-HCV positive patients and negative controls (AST antiHCV positive = 60.8 4.2 U/L; AST controls = 37.7 4.5 U/L; p 0.05). CONCLUSIONS: The prevalence of hepatitis C in densely populated metropolitan areas seems to be higher than previously expected (3.45% versus 0.4–0.7%). Revisiting the risk stratification and a more extensive screening might contribute to more effective prevention programs. The mere evaluation of transaminases is not suitable for predicting either seroprevalence of anti-HCV antibodies or chronic hepatitis C. Furthermore, the pre-clinical identification of HCV-positive individuals might significantly reduce the risk of accidental hepatitis C transmission among healthcare workers and would lead to an increase of the early hepatitis C diagnosis targeting to an early lead-in of the antiviral therapy avoiding late complications.