Seminars in medicine of the Beth Israel Hospital, Boston: Pancreatic and islet transplantation for diabetes--cures or curiosities?
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Blood Glucose↗
Biomedical subjects
R P Robertson
Publications and source records attributed to R P Robertson.
Preserved insulin secretion and insulin independence in recipients of islet autografts.
BACKGROUND: Transplantation of pancreatic islets, rather than whole pancreas, has been introduced as a treatment for diabetes mellitus. We studied five patients ranging in age from 12 to 37 years who had severe chronic pancreatitis for which they underwent total pancreatectomy followed by isolation and hepatic transplantation of their own islets. METHODS: All patients had remained insulin-independent for 1 to 7 1/2 years after transplantation. The numbers of islets transplanted ranged from 110,000 to 412,000. Islet function was assessed by measuring the plasma insulin responses to intravenous glucose and arginine and the plasma glucagon responses to hypoglycemia and arginine. In one patient, islet function was studied during catheterization of the hepatic vein, portal vein, and splenic artery and by analysis of a liver-biopsy specimen. RESULTS: After transplantation, the mean (+/- SD) fasting plasma glucose concentration was 122 +/- 47 mg per deciliter (6.8 +/- 2.6 mmol per liter) and the hemoglobin A1c concentration was 6.0 +/- 0.8 percent in the five patients. The values were most abnormal--214 mg per deciliter (11.9 mmol per liter) and 7.3 percent, respectively--in the patient who received only 110,000 islets. The acute plasma insulin responses to glucose and to arginine in the five patients were 23 +/- 13 and 26 +/- 10 microU per milliliter (168 +/- 94 and 184 +/- 70 pmol per liter), respectively, as compared with 58 +/- 6 and 37 +/- 8 microU per milliliter (416 +/- 44 and 267 +/- 61 pmol per liter) in the normal subjects. The peak plasma glucagon responses to insulin and arginine were 21 +/- 4 and 65 +/- 36 pg per milliliter, respectively, as compared with 125 +/- 28 and 156 +/- 99 pg per milliliter in the normal subjects. All five patients had plasma epinephrine but not pancreatic polypeptide responses to hypoglycemia. The results of the hepatic-vein catheterization in one patient indicated that the transplanted islets released insulin and glucagon in response to arginine. Immunoperoxidase staining of this patient's liver-biopsy specimen showed that the islets contained insulin, glucagon, and somatostatin but not pancreatic polypeptide. CONCLUSIONS: Intrahepatic transplantation of as few as 265,000 islets can result in the release of insulin and glucagon at appropriate times and in prolonged periods of insulin independence.
Adolescent↗
Defective insulin secretion in NIDDM: integral part of a multiplier hypothesis.
Non-insulin dependent diabetes mellitus (NIDDM) is characterized by a specific defect in glucose recognition by the pancreatic islet beta cell. This is in clear distinction to patients with insulin dependent diabetes mellitus (IDDM) who undergo pancreatic islet beta cell death and no longer have the ability to synthesize, store, and release insulin. Defective glucose-induced first phase insulin responses in patients with NIDDM can be partially restored by exogenous insulin treatment and by other pharmacologic therapy. These observations provide strength for the theory of glucose desensitization of the pancreatic beta cell as an important secondary defect in the pathogenesis of abnormal insulin secretion in NIDDM. However, even though defective insulin secretion is an essential part of the pathogenesis of NIDDM, in itself it is not sufficient. A multiplicative effect is required involving interaction between tissue resistance to insulin action and defective insulin secretion whose product is the syndrome of NIDDM.
Diabetes Mellitus, Type 2↗
Treatment of diabetes mellitus.
New treatment strategies for subjects with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus are being developed. Pilot studies utilising insulin itself have been reported to prevent Type 1 diabetes in subjects likely, by immunogenetic and physiologic criteria, to develop clinically overt disease, while the results of nicoti-namide trials in these subjects remain preliminary. Immunotherapy with cyclosporin A and azathioprine can slow disease progression and may produce long-term remissions when given within two months of onset of clinically overt disease. In subjects with established disease, familial clustering of diabetic nephropathy may be related to concomitant susceptibility to hypertension and elevated rates of Na/H countertransport. Treatment of hypertension associated with the nephropathy appears to slow renal deterioration. Whether reversal of the metabolic consequences of insulin deficiency or resistance also prevents chronic diabetic complications has not been firmly established. In the presence of a reduced Beta-cell mass, moderate hyperglycaemia may itself contribute to decreased muscle glucose uptake but not glycogen synthesis in Type 1 and Type 2 diabetes. Reversal of chronic hyperglycaemia by pancreas and islet cell transplantation, vanadate, and sulphonylureas are discussed as alternate strategies to insulin treatment in establishing normoglycaemia and furthering our understanding of insulin action and secretion at the cellular level. There remains a need to develop more sensitive biochemical and genetic markers to identify subjects at increased risk for developing chronic diabetic complications.
Animals↗
Pancreas transplantation as therapy for diabetes mellitus.
Pancreas transplantation, when successful, is the only reproducibly effective method to normalize glycemia without the use of exogenous insulin treatment in patients with diabetes mellitus. Worldwide success rates for combined pancreas and kidney transplantation are approximately 70%, and patient survival rates are approximately 90% one year postoperatively, although certain institutions have higher rates. Benefits of this procedure include normalization of fasting plasma glucose, hemoglobin A1C, glucose-induced insulin secretion, and intravenous glucose tolerance. Improvements are observed in glucose recovery following insulin-induced insulin hypoglycemia, glucagon secretion during hypoglycemia, kidney structure, and both motor and sensory nerve function. However, no benefits are accrued in pancreatic polypeptide secretion, kidney function, and the retinal pathology of diabetes mellitus. Further progress in these therapeutic results must await improvements in drugs for induction of immunosuppression, methods to induce immune tolerance, or provision of the operative procedure to patients less compromised preoperatively with secondary complications of diabetes.
Blood Glucose↗
Effects of hemipancreatectomy on pancreatic alpha and beta cell function in healthy human donors.
To assess the metabolic consequences of hemipancreatectomy in humans, we determined pancreatic beta and alpha cell function in healthy donors. Donors examined cross-sectionally were found to have significantly decreased glucose-induced phasic insulin secretion and arginine-induced insulin and glucagon secretion as compared to age, sex, and body index-matched controls. However, their fasting glucose and insulin values were not different from controls. Similar observations were found in the prospective evaluation of eight donors before and 15 +/- 2 mo after hemipancreatectomy. Beta cell reserve, as measured by glucose potentiation of arginine-induced insulin secretion, was significantly decreased in donors (maximal acute insulin response [AIRmax]: donors = 666 +/- 84 pM vs controls = 1,772 +/- 234 pM) while the PG50 (the glucose value at which the half-maximal response was observed) was the same in the two groups. Donors and controls responded to 60-min continuous intravenous infusions of glucose by reaching identical serum glucose values, despite significantly lower insulin secretory responses in donors. We conclude that hemipancreatectomy in human donors is associated with decreased pancreatic alpha and beta cell function. Since donors generally maintain normoglycemia after hemipancreatectomy despite diminished insulin secretion, our data suggest that healthy humans may compensate for hemipancreatectomy by increasing glucose disposal.
Adult↗
Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations.
Glucose toxicity of the pancreatic beta cell is considered to play a secondary role in the pathogenesis of type II diabetes mellitus. To gain insights into possible mechanisms of action of glucose toxicity, we designed studies to assess whether the loss of insulin secretion associated with serial passages of HIT-T15 cells might be caused by chronic exposure to high glucose levels since these cells are routinely cultured in media containing supramaximal stimulatory concentrations of glucose. We found that late passages of HIT cells serially cultured in media containing 11.1 mM glucose lost insulin responsivity and had greatly diminished levels of insulin content and insulin mRNA. In marked contrast, late passages of HIT cells cultured serially in media containing 0.8 mM glucose retained insulin mRNA, insulin content, and insulin responsivity to glucose in static incubations and during perifusion with glucose. No insulin gene mutation or alteration of levels of GLUT-2 were found in late passages of HIT cells cultured with media containing 11.1 mM glucose. These data uniquely indicate that loss of beta cell function in HIT cells passed serially under high glucose conditions is caused by loss of insulin mRNA, insulin content, and insulin secretion and is preventable by culturing HIT cells under low glucose conditions. This strongly suggests potential genetic mechanisms of action for glucose toxicity of beta cells.
Animals↗
G-proteins and hormonal inhibition of insulin secretion from HIT-T15 cells and isolated rat islets.
G-proteins are important mediators of hormonal inhibition of insulin secretion. To characterize the pertussis toxin-sensitive substrates present in HIT cell membranes, we performed immunoblots with specific antisera and found evidence for the presence of Gi alpha 1, Gi alpha 2, Gi alpha 3, and three forms of Go alpha. We observed that pertussis toxin-sensitive substrates mediate all of the effects of SRIF, and a major portion of the effects of EPI, on insulin secretion from rat islets during static incubations. These results agree with our previously reported studies examining phasic glucose-induced insulin secretion from HIT cells. To ascertain whether inhibition of adenylate cyclase, presumably involving coupling of the catalytic subunit to Gi, may be a common mechanism for both hormones, we studied the effects of 8-bromo-cyclic AMP and found that this agent partially prevented the inhibitory effects of both hormones. We also observed that the inhibitory effects of SRIF and EPI on insulin were nonadditive, that both hormones were additive to nickel chloride during inhibition of insulin release, and that they noncompetitively inhibited glipizide-induced insulin secretion through pertussis toxin-sensitive mechanisms. Together, these results suggest that both hormones exert their effects on insulin secretion at multiple G-protein-regulated sites including adenylate cyclase and sites distal to the glipizide-binding site on the KATP channel.
1-Methyl-3-isobutylxanthine↗
History of Diabetes, the Journal (1952-1991) editor's swan song.
Diabetes has provided scientific information in diabetes-related areas of basic and clinical research since 1952. This brief historical overview of the journal's activities and published articles is offered as an illustration of the remarkable strides in diabetes-related research that have taken place over the past 40 years.
Diabetes Mellitus↗
Gene expression of type I phospholipase A2 in pancreatic beta cells. Regulation of mRNA levels by starvation or glucose excess.
Messenger RNA from intact rat pancreatic islets, or from transformed hamster beta (HIT) cells, hybridized with the cDNA probe for type I (but not type II) phospholipase A2. The levels of phospholipase A2 mRNA increased in islets from fasted rats; they decreased in islets cultured in a high glucose concentration (control values at 5.5 mM glucose = 150 +/- 6% of those at 22 mM) which impaired subsequent insulin secretion (reduction in second-phase release = 70 +/- 11%). These studies uniquely demonstrate that type I phospholipase A2 is expressed specifically in beta cells and that nutrient availability modulates transcript levels, an effect which could that nutrient availability modulates transcript levels, an effect which could contribute to the detrimental influence of prolonged hyperglycemia on islet function.
Animals↗
[Hyperinsulinemia as a consequence of systemic venous drainage in patients with pancreas transplantation].
To evaluate the metabolic consequences of pancreatic transplantation with systemic venous drainage on beta cell function, we examined insulin and C-peptide responses to arginine and secretin in type I diabetic recipients of pancreas transplantation (n = 16), and normal controls (n = 28). Basal insulin levels were 24 +/- 3 microU/l in pancreas recipients, and 7 +/- 1 microU/l in controls (p less than 0.001). Stimulated insulin levels following arginine (MANOVA, p less than 0.001), and secretin (MANOVA, p less than 0.001) were 1.5 to 3 fold elevated compared to controls. In contrast, integrated C-peptide responses following stimulation with arginine or secretin did not differ significantly between the two groups. We conclude that recipients of pancreas allografts with systemic venous drainage have elevated basal and stimulated insulin levels and that these alterations are primarily due to alterations of first pass hepatic insulin clearance although insulin resistance secondary to immunosuppressive therapy (including prednisone) may also play a contributing role. To avoid hyperinsulinemia and its possible long term adverse consequences, transplantation of pancreas allografts in sites with portal rather than systemic venous drainage may be preferable.
Adult↗
Time-related, cross-sectional and prospective follow-up of pancreatic endocrine function after pancreas allograft transplantation in type 1 (insulin-dependent) diabetic patients.
It has been established that successful pancreas transplantation in Type 1 (insulin-dependent) diabetic patients results in normal but exaggerated phasic glucose-induced insulin secretion, normal intravenous glucose disappearance rates, improved glucose recovery from insulin-induced hypoglycaemia, improved glucagon secretion during insulin-induced hypoglycaemia, but no alterations in pancreatic polypeptide responses to hypoglycaemia. However, previous reports have not segregated the data in terms of the length of time following successful transplantation and very little prospective data collected over time in individual patients has been published. This article reports that in general there are no significant differences in the level of improvement when comparing responses as early as three months post-operatively up to as long as two years post-operatively when examining the data cross-sectionally in patients who have successfully maintained their allografts. Moreover, this remarkable constancy in pancreatic islet function is also seen in a smaller group of patients who have been examined prospectively at various intervals post-operatively. It is concluded that successful pancreas transplantation results in remarkable improvements in Alpha and Beta cell but not PP cell function that are maintained for at least one to two years.
Blood Glucose↗
Transfection with SV40 gene of human pancreatic endocrine cells.
At present, only islet cell lines of animal origin have been successfully generated (e.g. RIN, HIT). A fully differentiated human beta cell line would be advantageous for diabetes research. We now report the generation of a human endocrine pancreatic cell line obtained by transfection using a plasmid containing the early region of SV40 viral DNA. Viral integration and transcription was assessed by Southern and Northern blotting. This cell line has been growing continuously for more than 2 years and maintains several of the characteristics of the parental cells from which they were generated. The presence of Neuron Specific Enolase, Protein Gene Product 9.5, cytokeratin, microvilli, cytoplasmic electrodense granules and the secretion of insulin, glucagon and somatostatin supports the neuroendocrine origin of this cell line. However, hormone production progressively decreased and finally stopped at passage 8. Flow cytometric analysis showed that HLA expression in this cell line is readily induced by IFN-gamma and modulated by TNF-alpha. The establishment of this human endocrine cell line indicates the feasibility of immortalizing human islets by transfection with viral oncogenes. To obtain a fully differentiated cell line it may be necessary to use other DNA constructs which immortalize the cells without fully transforming their phenotype.
Antigens, Viral, Tumor↗
Pancreatic endocrine function in cystic fibrosis.
To characterize pancreatic endocrine secretion and to examine interrelationships among alterations in alpha, beta, and pancreatic polypeptide cell function in patients with cystic fibrosis (CF), we studied 19 patients with exocrine insufficiency (EXO), including 9 receiving insulin therapy (EXO-IT); 10 patients with no exocrine insufficiency (NEXO); and 10 normal control subjects. First-phase C-peptide response to intravenously administered glucose was significantly impaired in CF patients with exocrine insufficiency (EXO-IT = 0.02 +/- 0.01; EXO = 0.11 +/- 0.02; NEXO = 0.25 +/- 0.05; control subjects = 0.30 +/- 0.04 nmol/L). Lowering fasting glucose levels with exogenous insulin administration in EXO-IT did not improve beta cell responsivity to glucose. The C-peptide response to arginine was less impaired (EXO-IT = 0.12 +/- 0.02; EXO = 0.15 +/- 0.02; NEXO = 0.23 +/- 0.06; control subjects = 0.28 +/- 0.04 nmol/L). Alpha cell function, measured as peak glucagon secretion in response to hypoglycemia, was diminished in EXO but not NEXO (EXO-IT = 21 +/- 10; EXO = 62 +/- 19; NEXO = 123 +/- 29; control subjects = 109 +/- 12 ng/L). Despite diminished glucagon response, EXO patients recovered normally from hypoglycemia. Peak pancreatic polypeptide response to hypoglycemia distinguished CF patients with exocrine insufficiency from those without exocrine insufficiency (EXO-IT = 3 +/- 2; EXO = 3 +/- 1; NEXO = 226 +/- 68; control subjects = 273 +/- 100 pmol/L). Thus CF patients with exocrine disease have less alpha, beta, and pancreatic polypeptide cell function than CF patients without exocrine disease. These data suggest either that exocrine disease causes endocrine dysfunction in CF or that a common pathogenic process simultaneously and independently impairs exocrine and endocrine function.
Adult↗
Preventive effects of octreotide (SMS 201-995) on diabetic ketogenesis during insulin withdrawal.
1. Exogenous somatostatin inhibits glucagon secretion and prevents ketoacidosis in diabetic patients, but has the therapeutic disadvantage of requiring continuous intravenous infusion to exhibit these effects. 2. Consequently, we examined the effect of subcutaneous administration of the long-acting somatostatin analogue octreotide (SMS 201-995) on early ketogenesis in diabetic ketoacidosis. On two separate occasions insulin was withdrawn over a period of 9 h from seven type I diabetic patients. On the second occasion the patients were given 50 micrograms octreotide s.c. before the insulin withdrawal and every 3 h during insulin withdrawal. 3. Differences in integrated free fatty acid responses (4706 +/- 1227 mumol l-1 h vs 3026 +/- 835 mumol l-1 h, AUC, P = NS) were not significant, but the peak increments of acetoacetate (1413 +/- 354 mumol l-1 vs 612 +/- 176 mumol l-1, P less than 0.05), beta-hydroxybutyrate (2180 +/- 475 mumol l-1 vs 922 +/- 246 mumol l-1, P less than 0.01) and the decrements in plasma bicarbonate (-8 +/- 1 mumol l-1 vs -4 +/- 1 mumol l-1, P less than 0.05) and pH (-0.07 +/- 0.01 vs -0.03 +/- 0.01, P less than 0.05) were significantly less with octreotide. 4. At the same time peak increments of glucagon were lower with octreotide treatment (329 +/- 206 pg ml-1 vs 39 +/- 30 pg ml-1, P less than 0.05). 5. We conclude that, despite accelerated lipolysis and provision of substrate for ketogenesis during insulin withdrawal, this somatostatin analogue significantly reduces ketogenesis resulting from insulin deprivation, probably secondary to decreasing glucagon secretion. This drug may be useful in short term prophylactic treatment of diabetic patients during periods of increased risk for ketoacidosis.
Adult↗
Somatostatin and epinephrine decrease insulin messenger ribonucleic acid in HIT cells through a pertussis toxin-sensitive mechanism.
The sites of action for somatostatin and epinephrine to inhibit insulin secretion have been reported to be exclusively in the exocytotic pathway. We used HIT cells, a clonal line of beta-cells, to examine whether these hormones might have as yet undescribed, nonexocytotic effects on insulin messenger RNA levels. We observed that both somatostatin and epinephrine not only inhibit insulin secretion (53 +/- 2% and 50 +/- 2% of control, respectively) but also decrease insulin mRNA levels (54 +/- 5% and 66 +/- 5% of control, respectively) and insulin content in HIT cells (61 +/- 2% and 51 +/- 1% of control, respectively). The latter two effects are discernible by 24 h, maximal by 48 h, and are prevented by preincubation of HIT cells with pertussis toxin. These new observations suggest that somatostatin and epinephrine negatively modulate insulin availability through a guanine nucleotide binding protein-mediated step in insulin synthesis before the exocytotic pathway. This general mechanism may allow these two hormones to serve as more long-term regulators of insulin availability in distinction to their shorter term and more readily reversible inhibitory effects on the exocytotic pathway.
Animals↗
G proteins and modulation of insulin secretion.
Guanine nucleotide-binding proteins (G proteins) are critically important mediators of many signal-transduction systems. Several important sites regulating stimulus-secretion coupling and release of insulin from pancreatic beta-cells are modulated by G proteins. Gs mediates increases in intracellular cAMP associated with hormone-induced stimulation of insulin secretin. Gi mediates decreases in intracellular cAMP caused by inhibitors of insulin secretion, e.g., epinephrine, somatostatin, prostaglandin E2, and galanin. G proteins also regulate ion channels, phospholipases, and distal sites in exocytosis. Cholera and pertussis toxins irreversibly ADP ribosylate G proteins and are important tools that can be used both to manipulate G-protein-dependent modulators of insulin secretion and detect and quantify G proteins by electrophoretic techniques. The stage is set to pursue these initial observations in greater depth and ascertain whether G-protein research will provide important new insights into normal and abnormal regulation of insulin secretion.
Animals↗
Dysregulated release and degradation of insulin during mononuclear cell-induced beta-cell lysis in HIT cells.
Activated human mononuclear cells (MCs) were coincubated for 8 h with HIT cells, a clonal cell line of pancreatic islet beta-cells. Measurements of HIT cell viability and insulin secretion were determined to 1) ascertain whether activated MCs can alter beta-cell viability in the absence of exogenously provided cytokines, 2) examine this response over a range of MC-HIT cell ratios, and 3) identify mechanisms responsible for altered insulin release consequent to MC-induced HIT cell damage. HIT cell viability was markedly decreased by activated MCs during an 8-h coincubation. HIT cell lysis could be attributed to activated natural killer cells, and lysis did not occur in the presence of activated T-lymphocyte clones. Activated MCs caused a marked early increase in insulin release from HIT cells (increase at 2 h: 7.75 +/- 0.16 nM for activated MCs, 2.66 +/- 0.09 nM for control; P less than 0.001). Insulin levels by the 8th h of the coincubation were significantly lower than the 2-h peak (4.33 +/- 0.13 vs. 7.75 +/- 0.16 nM, P less than 0.001). These changes in insulin were dependent on the ratio of activated MCs to HIT cells with the effects clearly evident at an activated MC-HIT cell ratio of greater than or equal to 10:1. Pretreatment of activated MCs and HIT cells with prostaglandin-synthesis inhibitors did not prevent the cytotoxic effects of activated MCs on HIT cells. Somatostatin did not inhibit the early exaggerated insulin release, suggesting that these increased insulin levels represented leakage of insulin from damaged HIT cells rather than functional insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Arachidonic Acids↗