胰高血糖素与2型糖尿病及其肾病的关系

胰高血糖素是调控糖代谢平衡的重要激素之一,血清胰高血糖素的异常升高与2型糖尿病的起始和进展相关.糖尿病肾病是糖尿病常见的微血管并发症之一,胰高血糖素及其受体信号系统可能在它的发生、发展中发挥重要作用.其可能机制是通过cAMP、一氧化氮和前列腺素等诱导肾小球高滤过,通过增加DNA和蛋白质的合成诱导系膜细胞的增生、肥大,并可与肾素-血管紧张素系统(RAS)相互作用,最终引起肾小球损伤.胰高血糖素及其受体可作为治疗2型糖尿病及其肾脏并发症的靶点.     

The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis

BackgroundAdvances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT.MethodsExpert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review.ResultsConsensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery.ConclusionsAgreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.     

Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes

Aims/Introduction

Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin‐dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo.

Methods

A total of 38 individuals with a complete lack of endogenous insulin (fasting C‐peptide <0.0066 nmol/L) and whose glycemic control was optimized with an insulin pump during hospitalization were retrospectively studied. The basal insulin requirement, time‐to‐time adjustment of the basal insulin infusion rate, prandial insulin requirement and fasting plasma glucagon were compared between patients with a total pancreatectomy (n = 10) and those with type 1 diabetes (n = 28) after achievement of optimal glycemic control.

Results

Total daily insulin (P = 0.03) and basal insulin (P = 0.000006), but not prandial insulin requirements, were significantly lower in total pancreatectomy patients than in type 1 diabetes patients. The basal percentage (basal insulin/total daily insulin) was also significantly lower in total pancreatectomy patients than in type 1 diabetes patients (15.8 ± 7.8 vs 32.9 ± 10.1%, P = 0.00003). An increase in the insulin infusion rate early in the morning was not necessary in most patients with a pancreatectomy. The fasting plasma glucagon concentration was significantly lower in total pancreatectomy patients than in type 1 diabetes patients (P = 0.00007), and was positively correlated with the basal insulin requirement (P = 0.038).

Conclusions

The difference in insulin requirements between total pancreatectomy and type 1 diabetes patients suggests a contribution of glucagon to the basal insulin requirement and dawn phenomenon.     

Impact of body mass index on complications following pancreatectomy: Ten-year experience at National Cancer Center in China

AIM: To examine the impact of body mass index(BMI)on outcomes following pancreatic resection in the Chinese population.METHODS: A retrospective cohort study using prospectively collected data was conducted at the Cancer Hospital of the Chinese Academy of Medical Sciences, China National Cancer Center. Individuals who underwent pancreatic resection between January2004 and December 2013 were identified and included in the study. Persons were classified as having a normal weight if their BMI was 24 kg/m2 and overweight/obese if their BMI was ≥ 24 kg/m2 as defined by the International Life Sciences Institute Focal Point in China. A χ 2 test(for categorical variables) or a t test(for continuous variables) was used to examine the differences in patients' characteristics between normal weight and overweight/obese groups. Multiple logistic regression models were used to assess the associationsof postoperative complications, operative difficulty,length of hospital stay, and cost with BMI, adjusting for age, sex, and type of surgery procedures.RESULTS: A total of 362 consecutive patients with data available for BMI calculation underwent pancreatic resection for benign or malignant disease from January1, 2004 to December 31, 2013. Of the 362 patients,156 were overweight or obese and 206 were of normal weight. One or more postoperative complications occurred in 35.4% of the patients following pancreatic resection. Among patients who were overweight or obese, 42.9% experienced one or more complications,significantly higher than normal weight(29.6%)individuals(P = 0.0086). Compared with individuals who had normal weight, those with a BMI ≥ 24.0kg/m2 had higher delayed gastric emptying(19.9% vs5.8%, P 0.0001) and bile leak(7.7% vs 1.9%, P =0.0068). There were no significant differences seen in pancreatic fistula, gastrointestinal hemorrhage, reoperation,readmission, or other complications. BMI did not show a significant association with intraoperative blood loss, operative time, length of hospital stay, or cost.CONCLUSION: Higher BMI increases the risk for postoperative complications after pancreatectomy in the Chinese population. The findings require replication in future studies with larger sample sizes.     

Dysregulated plasma glucagon levels in Japanese young adult type 1 diabetes patients

Currently, the clinical dynamics of glucagon need to be revised based on previous data obtained from conventional glucagon radioimmunoassays. In the present study, we evaluated plasma glucagon levels in type 1 diabetes patients using a newly‐developed sandwich enzyme‐linked immunosorbent assay, and its association with clinical parameters and markers of diabetes complications were statistically assessed. The plasma glucagon level in 77 Japanese type 1 diabetes patients was 28.1 ± 17.7 pg/mL, and comparable with that reported previously for type 2 diabetes patients. However, the values were widely spread and did not correlate with plasma glucose values. Additionally, the average glucagon levels in patients in a hypoglycemic state (glucose level <80 mg/dL) did not increase (21.7 ± 12.2 pg/mL). The average glucagon level of patients experiencing hypoglycemia unawareness was significantly lower. Plasma glucagon levels evaluated using the new enzyme‐linked immunosorbent assay were dysregulated in type 1 diabetes patients in respect to plasma glucose levels, suggesting dysregulation of secretion.     

Diagnosis and treatment of diabetes mellitus in chronic pancreatitis

Diabetes secondary to pancreatic diseases is commonly referred to as pancreatogenic diabetes or type 3c diabetes mellitus.It is a clinically relevant condition with a prevalence of 5%-10%among all diabetic subjects in Western populations.In nearly 80%of all type 3c diabetes mellitus cases,chronic pancreatitis seems to be the underlying disease.The prevalence and clinical importance of diabetes secondary to chronic pancreatitis has certainly been underestimated and underappreciated so far.In contrast to the management of type 1 or type2 diabetes mellitus,the endocrinopathy in type 3c is very complex.The course of the disease is complicated by additional present comorbidities such as maldigestion and concomitant qualitative malnutrition.General awareness that patients with known and/or clinically overt chronic pancreatitis will develop type 3c diabetes mellitus(up to 90%of all cases)is rather good.However,in a patient first presenting with diabetes mellitus,chronic pancreatitis as a potential causative condition is seldom considered.Thus many patients are misdiagnosed.The failure to correctly diagnose type 3 diabetes mellitus leads to a failure to implement an appropriate medical therapy.In patients with type 3c diabetes mellitus treating exocrine pancreatic insufficiency,preventing or treating a lack of fat-soluble vitamins(especially vitamin D)and restoring impaired fat hydrolysis and incretin secretion are key-features of medical therapy.     

Angiopathies in pancreatic diabetes resulting from chronic pancreatitis

Summary Conclusions. Marked diabetic micro- and macroangiopathies were recognized in three autopsy cases with pancreatic diabetes resulting from chronic pancreatitis. Background. Recent reports have suggested that diabetic retinopathy occurs as one of the microangiopathies in patients with secondary diabetes following chronic pancreatitis. Methods. We report three autopsy cases with pancreatic diabetes. Cases 1 and 2 showed alcoholic chronic pancreatitis. Case 3 was a patient with chronic pancreatitis resulting from hyperparathyroidism. All three cases had pancreatic calcification and markedly decreased exocrine pancreatic function. There was no family history of diabetes in these patients. The HbA₁ values were elevated, with diminished secretion of both insulin and glucagon. Results. The common features of the clinical courses were poor glycemic control, including insulin-induced hypoglycemic attacks in the early stage and microangiopathy, followed by difficulties in treatment for hypertension in the late stage of pancreatic diabetes. Autopsies, performed after 12–18 yr of diabetes, revealed fibrosis of the pancreas, disappearance of acinar cells in the exocrine pancreas, atrophy, a diminished number of islets of Langerhans, and diabetic glomerulosclerosis, with arteriosclerosis in the brain, heart, and kidneys. Cerebral hemorrhage, heart failure, and myocardial infarction were suggested to be the main causes of death. Although the serum lipid levels were rather low in cases 1 and 2, arteriosclerosis was marked by the age of 60, and serum protein levels were also low in all three cases.     

Glucagon and insulin secretion in potential diabetes

Summary Insulin and glucagon have been studied in 20 subjects (both of the subjects’ parents were diabetic or in case of only one diabetic parent, the other showed a first degree familiarity of diabetes): 10 showed normal glucose tolerance (‘true prediabetics’) and 10 impaired glucose tolerance (‘genetic chemical diabetes’). Mean insulin response to oral (100 g) and i.v. glucose load (200 mg/kg followed by 20 mg/kg/min for 60 min) and to arginine infusion (25 g in 30 min) was normal in the prediabetics and delayed and higher in the subjects with chemical diabetes as compared to the control group. Glucagon response to arginine was higher, but not significantly, in prediabetics and in subjects with chemical diabetes. In both of these groups glucagon suppression by glucose was not observed. The insulin/glucagon molar ratio was significantly reduced after glucose infusion in these two groups. No correlation was found between insulin and glucagon secretion after arginine or glucose. A possible alteration in the mechanism controlling glucagon secretion even in the earliest phases of diabetes is suggested. This work was supported in part by C.N.R. (Consiglio Nazionale delle Ricerche), Roma, grant # CT 76.01345.04.     

Plasmatic arginine vasopressin levels in total and partial diabetes insipidus

Plasma arginine vasopressin (AVP) was measured in 24 patients with polyuria exceeding 3.5 l/day diagnosed as severe or partial diabetes insipidus according to the dehydration test. All patients with severe diabetes insipidus diagnosed by the dehydration test had very low or undetectable basal AVP values and always subnormal plasma osmolality. Patients with partial diabetes insipidus diagnosed by the dehydration test had a wide range of AVP and osmolality values. The stimulation test performed on these patients was able to differentiate patients with primary polydipsia from patients with partial diabetes insipidus. The measurement of basal plasma AVP is capable of diagnosing all patients with severe diabetes insipidus; when we combine the stimulation test with the measurement of AVP, we can differentiate partial diabetes insipidus from other forms of polyuria.     

Low serum trypsinogen levels in chronic pancreatitis: Correlation with parenchymal loss,exocrine pancreatic insufficiency,and diabetes but not CT-based cambridge severity scores for fibrosis

BackgroundChronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas affecting acinar cells, duct cells, islet cells and inflammatory cells including fibrosis-producing stellate cells. Serum trypsinogen is a biomarkers of acinar cell function.AimTo define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP.MethodsSerum samples from previously ascertained and well phenotyped case and control subjects from the North American Pancreatitis Study II (NAPS2) were used to measure serum trypsinogen levels in a commercial laboratory. Control samples were used to define normal ranges and compared with levels in CP patients with defined features.ResultsA final cohort of 279 CP patients and 262 controls from the NAPS2 studies were evaluated. In controls trypsinogen had a mean of 34.96 ng/ml and SD = 11.99. Cut-off values for low trypsinogen ranged from <20 to 10 ng/ml and very low trypsinogen at <10 ng/ml. Compared to controls, CP was associated with very low trypsinogen levels (p < 0.0001). Within CP, very low trypsinogen levels correlated with parenchymal loss (pancreatic surgery [p < 0.05]; atrophy with calcifications, [p < 0.001]), EPI (p < 0.01, trend p < 0.001) and diabetes (trend p < 0.01) but not CT-based criteria for fibrosis (pancreatic duct dilation, irregularity, strictures).ConclusionsVery low serum trypsinogen levels correlate with measures of acinar cell loss including surgical resection, atrophic-calcific CP, diabetes and functional symptoms EPI but not duct morphology criteria. Serum trypsinogen levels correlate with decreased acinar cell function and therefore have biomarker utility clinical management.     

Imaging prediction of islet yield and post-operative insulin requirement in children undergoing total pancreatectomy with islet autotransplantation

BackgroundPredicting post-operative glycemic control in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) remains difficult. The purpose of our study was to explore preoperative imaging as a marker for islet yield and insulin need in pediatric patients undergoing TPIAT.MethodsThis was a retrospective study of children (≤18 years) who had undergone TPIAT between April 2015 and December 2018 and had 6 or more months of post-TPIAT follow-up. Patient specific factors (height, weight, body mass index [BMI], body surface area [BSA]) and pancreas volume segmented from the most recent pre-operative cross-sectional imaging were explored as predictors of islet yield (total islet counts [TIC], total islet equivalents [TIE], islet equivalents per kilogram body weight [IEQ/kg]) and glycemic control (total daily dose of insulin per kilogram body weight [TDD/kg], insulin independence) using Pearson correlation and univariate and multiple regression.ResultsThirty-three patients, median age 13 years (IQR: 10–15 years), 64% female (21/33) met inclusion criteria. Nine patients (27%) achieved insulin independence at six months. Median TIE isolated was 310,000 (IQR: 200,000–460,000). Segmented pancreas volume was moderately associated with TIE (coefficient estimate = 0.34, p = 0.034). On multiple regression analysis, there was no significant predictor of insulin independence but number of attacks of pancreatitis (estimate = 0.024; p = 0.018) and segmented pancreas volume by body weight (estimate = ?0.71; p < 0.001) were significant predictors of insulin TDD/kg.ConclusionPancreas volume segmented from pre-TPIAT imaging has predictive performance for post-TPIAT insulin need in children.     

Induction of insulin-dependent diabetes mellitus by total pancreatectomy for pancreatic islet transplantation in cynomolgus monkeys

Background/purpose

In order to perform a preclinical trial of pancreatic islet transplantation (PIT) in nonhuman primates, insulin-dependent diabetes mellitus (IDDM) must be induced. Methods for IDDM induction are administration of streptozotocin (STZ) or total pancreatectomy (TP). While STZ-induced IDDM is not always reliable, TP is appropriate for IDDM induction. However, TP is very difficult because of the complex surgical procedure required, necessary confirmation of IDDM, and difficulty in postoperative management. In this study, we tried to establish a reliable IDDM model for PIT in cynomolgus monkeys.

Methods

TP was performed in 5 male cynomolgus monkeys (Macaca fascicularis). This was followed by scheduled measurements of blood glucose, C-peptide levels, insulin levels, oral intake, and insulin requirements. IDDM induction was confirmed by serum C-peptide levels and intravenous glucose tolerance test (IVGTT). Allogeneic PIT was performed 14?days later with immunosuppressive therapy.

Results

TP successfully induced IDDM in all animals, confirmed by reduction of fasting serum C-peptide levels. Negative responses of serum C-peptide levels and insulin in IVGTT provided further confirmation of IDDM induction. No mortality or morbidity was encountered in any of the animals.

Conclusions

TP successfully induced IDDM for PIT in cynomolgus monkeys.     

Glucagon physiology and pathophysiology in the light of new advances

Summary Recent advances in the understanding of glucagoninsulin relationships at the level of the islets of Langerhans and of hepatic fuel metabolism are reviewed and their impact on our understanding of glucagon physiology and pathophysiology is considered. It now appears that cells can respond directly to hyperglycaemia in the absence of insulin and cells, but that antecedent hyperglycaemia masks or attenuates this response. Insulin appears to exert ongoing release inhibition upon glucagon secretion, probably via the intra-islet microvascular system that connects cells to cells. Diabetic hyperglucagonemia in insulin deficient states appears to be secondary to lack of the restraining influence of insulin. The cell response to glucopenia, by contrast, may be in large part mediated by release of noradrenaline from nerve endings in contact with cells. Glucagon's action on glucose and ketone production by hepatocytes is mediated by increase in cyclic-AMP-dependent protein kinase. The opposing action of insulin upon glucagon-mediated events probably occurs largely at this level. Consequently, when glucagon secretion or action is blocked, cyclic-AMP-dependent protein kinase activity is low even in the absence of insulin, explaining why marked glucose and ketone production is absent in bihormonal deficiency states.     

Lack of suppression of plasma glucagon levels in late pregnancy persists postpartum only in women with previous gestational diabetes mellitus

Abstract The aim of the present study was to examine fasting (0) and postglucose glucagon levels in normal and gestational diabetes mellitus (GDM) pregnancy, as available data are somewhat conflicting. To this end we studied 18 women with GDM at 26–32 weeks of pregnancy and compared these with 26 normal pregnant women matched for age and BMI. We also examined glucagon suppressibility postpartum (2–4 months) in the same ex-GDM women, in whom normal glucose tolerance was confirmed (WHO criteria) and compared these with 17 controls matched for age and BMI. Glucose, insulin and glucagon levels were measured during a 100 or 75 g oral glucose tolerance test (OGTT) respectively. In pregnant women, baseline and 3 h after glucose ingestion, plasma glucagon levels were significantly higher (p<0.05) in women with GDM compared to normal women. Interestingly, in normal pregnancy a significant increase (p<0.01) of postglucose plasma glucagon levels at 1 and 2 h compared to baseline levels was observed, while there was no change in GDM pregnancy. In postpartum euglycaemic women, there was no difference in basal glucagon levels between the two groups. A differential glucagon response during OGTT was observed: in control women there was a significant glucagon suppression (p<0.01) at 2 h, while there was a significant glucagon increase (p<0.01) 1 h after glucose ingestion, in ex-GDM women. We conclude that (a) absence of the suppressibility of glucagon in ex-GDM women with normal OGTT may indicate insulin resistance and might be involved in the natural history towards glucose intolerance; and (b) nonsuppression of glucagon in normal late pregnancy as well as in pregnancy complicated by GDM may be due to physiological insulin resistance of the cells during this period.     

Optimal duration of the early and late recurrence of pancreatic cancer after pancreatectomy based on the difference in the prognosis

BackgroundThe term “early recurrence” of pancreatic cancer has not been well-defined in most previous studies.MethodsThe clinical records of 86 patients who underwent macroscopic curative pancreatectomy for pancreatic cancer between 2000 and 2009 were retrospectively examined. We divided 55 patients who experienced disease recurrence into two groups, the early and late recurrence groups, using the minimum p value approach. The relationships between the interval prior to recurrence and clinical outcomes were investigated.ResultsThe cumulative 5-year overall survival rates for all 86 patients were 30.2%. For 55 patients who experienced disease recurrence, the optimal cut-off value for differentiating early (n = 37) and late (n = 18) recurrence based on the overall survival was 12 months (p = 0.0000045). The Cox proportional hazard analysis identified carbohydrate antigen 19-9 > 100 U/ml (p = 0.017) and surgical margin (p = 0.007) as the independent prognostic factors associated with overall survival. Positive surgical margin (p = 0.037) and severe venous invasion (p = 0.005) were identified as independent factors associated with early recurrence.ConclusionTwelve months after pancreatectomy is the optimal cut-off value for defining early versus late recurrence based on the overall survival. Early recurrence was related to the status of the surgical margin and venous invasion.