Restored hypoglycemic counterregulation is stable in successful pancreas transplant recipients for up to 19 years after transplantation

BACKGROUND: Pancreas transplantation has been shown to fully restore glucagon response and partially restore epinephrine response to hypoglycemia during the first few years after transplantation in patients with type 1 diabetes. However, prior studies have not examined hypoglycemic counterregulation in any pancreas transplant recipient of more than 6 years' duration. METHODS: To determine whether restoration of hypoglycemic counterregulation is maintained over a prolonged period after transplantation, we studied counterregulatory responses and symptom recognition in two groups of pancreas transplant recipients using a stepped hypoglycemic, hyperinsulinemic clamp. Group 1 consisted of 11 successful transplant recipients of 11 to 19 years' duration (mean+/-SE, 13.9+/-0.7 years). Group 2A consisted of seven successful pancreas transplant recipients of 5 to 11 years' duration (mean+/-SE, 8.7+/-0.9 years) who had been studied approximately 5 years earlier using the same stepped, hypoglycemic clamp technique. RESULTS: Both groups had significant rises in plasma glucagon during the hypoglycemic clamp similar to that seen in short-term recipients and normal controls. Both groups also had significant increases in plasma epinephrine responses similar to that seen in short-term transplant recipients but less than that of normal control subjects. The mean symptom scores of group 1 were significantly less than those of the control group at glucose levels of 60 and 50 mg/dL but not at 40 mg/dL. The mean symptom scores of group 2A were not significantly different than that of control subjects. CONCLUSION: These results indicate that the restoration of hypoglycemic counterregulation by pancreas transplantation remains stable in successful pancreas transplant recipients for up to 19 years after transplantation.     

Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes

Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.     

Glucagon,catecholamine, and symptom responses to hypoglycemia in living donors of pancreas segments

Donors undergoing hemi-pancreatectomy to provide a pancreas segment for transplantation into a relative with type 1 diabetes acquire diminished insulin and glucagon responses to intravenous agonists. Some donors develop diabetes and require treatment for hyperglycemia. They become at risk for hypoglycemia when treatment includes sulfonylureas and insulin. However, no studies assessing the impact of hemi-pancreatectomy in humans on islet alpha-cell responses to hypoglycemia have been reported. Consequently, we performed stepped hypoglycemic clamps in 7 donors of varying glycemic control and compared their responses to 16 control subjects. Donors and control subjects reached similar nadirs of glycemia (45 +/- 3 and 41 +/- 1 mg/dl, respectively) during the clamp. The donors had significantly higher mean basal glucagon levels than control subjects (203 +/- 27 vs. 135 +/- 15 pg/ml; P < 0.03) but did not have significant differences in glucagon responses during the clamp. The donors also had significantly higher mean peak epinephrine responses during the clamp (1,231 +/- 134 vs. 730 +/- 68 pg/ml; P < 0.002), but there were no statistically significant differences in norepinephrine or symptom responses. The glucose thresholds at which hormonal and symptom responses began were not different. We conclude that although glucagon response to arginine and insulin response to glucose and arginine are diminished after hemi-pancreatectomy, no deficiency in glucagon responses were detected during hypoglycemia.     

Cortisol elevations comparable to those that occur during hypoglycemia do not cause hypoglycemia-associated autonomic failure

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural and adrenomedullary response and the resulting neurogenic [autonomic] symptom responses) and thus causes a vicious cycle of recurrent hypoglycemia. To assess the suggestion that it is the cortisol response to antecedent hypoglycemia that mediates HAAF, we tested the hypothesis that plasma cortisol elevations during euglycemia that are comparable to those that occur during hypoglycemia reduce sympathoadrenal and neurogenic symptom responses to subsequent hypoglycemia. To do this, 12 healthy subjects were studied with hyperinsulinemic-stepped hypoglycemic clamps the day after saline or cortisol (1.3 +/- 0.2 micro g. kg(-1) x min(-1)) infusions from 0930 to 1200 and from 1330 to 1600. Compared with saline, antecedent cortisol elevations did not reduce the sympathoadrenal (e.g., final plasma epinephrine levels of 674 +/- 84 vs. 606 +/- 80 pg/ml and final plasma norepinephrine levels of 332 +/- 26 vs. 304 +/- 26 pg/ml) or neurogenic symptom (e.g., final scores of 9.3 +/- 1.1 vs. 13.2 +/- 1.3) responses to subsequent hypoglycemia. Thus, these data do not support the suggestion that cortisol mediates HAAF.     

Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulin-induced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA1c 6.5 +/- 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 +/- 4 mg/dl) or hypoglycemia (plasma glucose 58 +/- 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 +/- 38 vs. 2,785 +/- 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 +/- 0.2 vs. 2.5 +/- 0.3 nmol/l, and glucagon 38 +/- 7 vs. 92 +/- 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 +/- 0.14 mg x kg(-1) x min(-1) during euglycemia yet approximately 50% higher with hypoglycemia [1.30 +/- 0.20 mg x kg(-1) x min(-1)], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 +/- 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 +/- 14 to 234 +/- 10 mmol/l (P < 0.001) and accounted for approximately 100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 +/- 23 mmol/l) was significantly lower than in nondiabetic subjects (316 +/- 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 +/- 22 vs. 448 +/- 16 pmol/l in hypoglycemia and 0.9 +/- 0.3 vs. 1.6 +/- 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 +/- 0.5 vs. 1.2 +/- 0.3 mg x kg(-1) x min(-1) compared with euglycemia, P = NS), and hepatic glycogen concentration did not change significantly with hypoglycemia. We conclude that glycogenolysis accounts for the majority of EGP during the first 90 min of hypoglycemia in nondiabetic subjects. In intensively treated type 1 diabetes, despite some activation of counterregulation, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of EGP, factors that may contribute to the defective counterregulation seen in such patients.     

Restoration of Glucose Counterregulation by Islet Transplantation in Long-standing Type 1 Diabetes

Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ∼30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-²H₂-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA_1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia.     

Hypoglycemia-associated autonomic failure in advanced type 2 diabetes

We tested the hypotheses that the glucagon response to hypoglycemia is reduced in patients who are approaching the insulin-deficient end of the spectrum of type 2 diabetes and that recent antecedent hypoglycemia shifts the glycemic thresholds for autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia to lower plasma glucose concentrations in type 2 diabetes. Hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) were performed on two consecutive days, with an additional 2 h of hypoglycemia (50 mg/dl) in the afternoon of the first day, in 13 patients with type 2 diabetes---7 treated with oral hypoglycemic agents (OHA R(X); mean [+/- SD] HbA(1c) 8.6 +/- 1.1%) and 6 requiring therapy with insulin for an average of 5 years and with reduced C-peptide levels (insulin R(X), HbA(1c) 7.5 +/- 0.7%)---and 15 nondiabetic control subjects. The glucagon response to hypoglycemia was virtually absent (P = 0.0252) in the insulin-deficient type 2 diabetic patients (insulin R(X) mean [+/- SE] final values of 52 plus minus 16 vs. 93 plus minus 15 pg/ml in control subjects and 98 +/- 16 pg/ml in type 2 diabetic patients, OHA R(X) on day 1). Glucagon (P = 0.0015), epinephrine (P = 0.0002), and norepinephrine (P = 0.0138) responses and neurogenic (P = 0.0149) and neuroglycopenic (P = 0.0015) symptom responses to hypoglycemia were reduced on day 2 after hypoglycemia on day 1 in type 2 diabetic patients; these responses were not eliminated, but their glycemic thresholds were shifted to lower plasma glucose concentrations. In addition, the glycemic thresholds for these responses were at higher-than-normal plasma glucose concentrations (P = 0.0082, 0.0028, 0.0023, and 0.0182, respectively) at baseline (day 1) in OHA R(X) type 2 diabetic patients, with relatively poorly controlled diabetes. Because the glucagon response to falling plasma glucose levels is virtually absent and the glycemic thresholds for autonomic and symptomatic responses to hypoglycemia are shifted to lower glucose concentrations by recent antecedent hypoglycemia, patients with advanced type 2 diabetes, like those with type 1 diabetes, are at risk for hypoglycemia-associated autonomic failure and the resultant vicious cycle of recurrent iatrogenic hypoglycemia.     

Atrial natriuretic peptide in diabetic and nondiabetic patients with and without heart transplantation

BACKGROUND: Natriuretic peptides are useful markers for risk stratification of patients with heart disease. However, conflicting results have been reported about circulating atrial natriuretic peptide (ANP) concentration in heart transplant recipients. METHODS: To ascertain the effects of diabetes and acute insulin administration on plasma ANP concentrations in a model of heart denervation, we studied 12 diabetic (D-OHT) and 6 nondiabetic heart-transplanted (OHT) patients using the euglycemic-hyperinsulinemic clamp and oral glucose tolerance tests. Five patients with type 2 diabetes without heart transplantation (D) and 9 healthy subjects (NOR) matched for anthropometric features served as the controls. RESULTS: Means baseline plasma ANP concentration was higher in D-OHT (82 +/- 15 pg/mL) than in OHT or NOR (27 +/- 4 or 30 +/- 5; P < .01), but was not different than D (69 +/- 12; P = .82). During the clamp plasma ANP showed similar increases in all groups (49 +/- 4, 39 +/- 3, 59 +/- 4, and 49 +/- 3% in D-OHT, OHT, D, and NOR; P < .02 vs basal, P = NS among groups). Plasma osmolarity and catecholamines were also not different among groups and did not increase during the clamp. Fasting plasma ANP concentrations correlated with plasma glucose concentrations measured 120 minutes after oral glucose tolerance testing. CONCLUSIONS: Among heart transplantation recipients fasting plasma ANP concentrations were not different at 5 to 6 years after the surgical procedure than in nondiabetic controls. Increased ANP concentrations were observed among recipients with diabetes and among nontransplanted diabetic patients. Although the insulin-induced increment in ANP concentrations was not different among groups, circulating ANP was strongly associated with glucose tolerance status.     

Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients

To evaluate the metabolic consequences of pancreas transplantation with systemic venous drainage on beta-cell function, we examined insulin and C-peptide responses to glucose and arginine in type I (insulin-dependent) diabetic pancreas recipients (n = 30), nondiabetic kidney recipients (n = 8), and nondiabetic control subjects (n = 28). Basal insulin levels were 66 +/- 5 pM in control subjects, 204 +/- 18 pM in pancreas recipients (P less than 0.0001 vs. control), and 77 +/- 17 pM in kidney recipients. Acute insulin responses to glucose were 416 +/- 44 pM in control subjects, 763 +/- 91 pM in pancreas recipients (P less than 0.01 vs. control), and 589 +/- 113 pM in kidney recipients (NS vs. control). Basal and stimulated insulin levels in two pancreas recipients with portal venous drainage were normal. Integrated acute C-peptide responses were not statistically different (25.3 +/- 4.3 nM/min in pancreas recipients, 34.2 +/- 5.5 nM/min in kidney recipients, and 23.7 +/- 2.1 nM/min in control subjects). Similar insulin and C-peptide results were obtained with arginine stimulation, and both basal and glucose-stimulated insulin-C-peptide ratios in pancreas recipients were significantly greater than in control subjects. 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) probably plays a contributing role. To avoid hyperinsulinemia and its possible long-term adverse consequences, transplantation of pancreas allografts into sites with portal rather than systemic venous drainage should be considered.     

Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia

Given that iatrogenic hypoglycemia often occurs during the night in people with type 1 diabetes, we tested the hypothesis that physiological, and the resulting behavioral, defenses against developing hypoglycemia-already compromised by absent glucagon and attenuated epinephrine and neurogenic symptom responses-are further compromised during sleep in type 1 diabetes. To do so, we studied eight adult patients with uncomplicated type 1 diabetes and eight matched nondiabetic control subjects with hyperinsulinemic stepped hypoglycemic clamps (glucose steps of approximately 85, 75, 65, 55, and 45 mg/dl) in the morning (0730-1230) while awake and at night (2100-0200) while awake throughout and while asleep from 0000 to 0200 in random sequence. Plasma epinephrine (P = 0.0010), perhaps norepinephrine (P = 0.0838), and pancreatic polypeptide (P = 0.0034) responses to hypoglycemia were reduced during sleep in diabetic subjects (the final awake versus asleep values were 240 +/- 86 and 85 +/- 47, 205 +/- 24 and 148 +/- 17, and 197 +/- 45 and 118 +/- 31 pg/ml, respectively), but not in the control subjects. The diabetic subjects exhibited markedly reduced awakening from sleep during hypoglycemia. Sleep efficiency (percent time asleep) was 77 +/- 18% in the diabetic subjects, but only 26 +/- 8% (P = 0.0109) in the control subjects late in the 45-mg/dl hypoglycemic steps. We conclude that autonomic responses to hypoglycemia are reduced during sleep in type 1 diabetes, and that, probably because of their reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia. Thus both physiological and behavioral defenses are further compromised during sleep. This sleep-related hypoglycemia-associated autonomic failure, in the context of imperfect insulin replacement, likely explains the high frequency of nocturnal hypoglycemia in type 1 diabetes.     

Successful islet transplantation from nonheartbeating donor pancreata using modified Ricordi islet isolation method

BACKGROUND: Current success of islet transplantation has led to donor shortage and the need for marginal donor utilization to alleviate this shortage. The goal of this study was to improve the efficacy of islet transplantation using nonheartbeating donors (NHBDs). METHODS: First, we used porcine pancreata for the implementation of several strategies and applied to human pancreata. These strategies included ductal injection with trypsin inhibitor for protection of pancreatic ducts, ET-Kyoto solution for pancreas preservation, and Iodixanol for islet purification. RESULTS: These strategies significantly improved both porcine and human islet isolation efficacy. Average 399,469+/-36,411 IE human islets were obtained from NHBDs (n=13). All islet preparations met transplantation criteria and 11 out of 13 cases (85%) were transplanted into six type 1 diabetic patients for the first time in Japan. All islets started to secrete insulin and all patients showed better blood glucose control without hypoglycemic loss of consciousness. The average HbA1c levels of the six recipients significantly improved from 7.5+/-0.4% at transplant to 5.1+/-0.2% currently (P<0.0003). The average insulin amounts of the six recipients significantly reduced from 49.2+/-3.3 units at transplant to 11+/-4.4 units (P<0.0005) and five out of six patients reduced to less than half dose. The first patient is now insulin free, the first such case in Japan. CONCLUSION: This demonstrates that our current protocol makes it feasible to use NHBDs for islet transplant into type 1 diabetic patients efficiently.     

Glucose counterregulation in patients after pancreatectomy. Comparison with other clinical forms of diabetes

Glucose and counterregulatory hormone responses to a high-dose (1.7 mU/kg/min) insulin infusion were studied in 6 patients who had undergone total pancreatectomy, and the results were compared with those of normal controls and patients with other clinical forms of diabetes. The maximum increase in the plasma glucagon concentration during hypoglycemia in the pancreatectomized patients (5 +/- 5.6 pg/ml) was less than in normals (121 +/- 22 pg/ml). Type I diabetic subjects (28 +/- 14 pg/ml), and insulin-treated diabetic subjects of recent onset (36 +/- 12 pg/ml) also had reduced responses, while responses were normal in type II diabetic subjects (102 +/- 26 pg/ml). The epinephrine response to the hypoglycemic stimulus was reduced after pancreatectomy (278 +/- 81 pg/ml) and in type I diabetic subjects (628 +/- 244 pg/ml), but was not different from control (858 +/- 126 pg/ml) in type II and recent-onset diabetic patients. There was considerable overlap in counterregulatory hormone responses in individual patients with and without autonomic neuropathy and with normal or undetectable fasting C-peptide concentrations. While the control subjects all experienced symptoms of hypoglycemia within a narrow range of plasma glucose concentrations (35-46 mg/dl), five of the diabetic subjects experienced symptoms of hypoglycemia at plasma glucose levels of greater than or equal to 55 mg/dl, and five had no subjective awareness of hypoglycemia despite plasma glucose levels less than 30 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fructose normalizes specific counterregulatory responses to hypoglycemia in patients with type 1 diabetes

We have previously reported that specific counterregulatory responses to hypoglycemia were augmented by an infusion of fructose in nondiabetic humans. We hypothesized that this effect was due to the interaction of a "catalytic" dose of fructose with the regulatory protein for glucokinase in glucose-sensing cells that drive counterregulation. To examine whether fructose could restore counterregulatory responses in type 1 diabetic patients with defective counterregulation, we performed stepped hypoglycemic clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/l glucose steps, 50 min each) in eight intensively treated patients (HbA(1c) 6.4 +/- 0.7%) on two separate occasions: without (control) or with coinfusion of fructose (1.2 mg . kg(-1) . min(-1)). Fructose induced a resetting of the glycemic threshold for secretion of epinephrine to higher plasma glucose concentrations (from 3.3 +/- 0.1 to 3.9 +/- 0.1 mmol/l; P = 0.001) and markedly augmented the increment in epinephrine (by 56%; P < 0.001). The amplification of epinephrine responses was specific; plasma norepinephrine, glucagon, growth hormone, and cortisol were unaffected. Hypoglycemia-induced endogenous glucose production ([3-(3)H]-glucose) rose by 90% (P < 0.001) in the fructose studies, compared with -2.0% (NS) in control. In concert, the glucose infusion rates during the 3.9- and 3.3-mmol/l steps were significantly lower with fructose (2.3 +/- 0.6 and 0.0 +/- 0.0 vs. 5.9 +/- 1.15 and 3.9 +/- 1.0 micromol . kg(-1) . min(-1), respectively; P < 0.001 for both), indicating the more potent counterregulatory response during fructose infusion. We conclude that infusion of fructose nearly normalizes the epinephrine and endogenous glucose production responses to hypoglycemia in type 1 diabetic patients with impaired counterregulation, suggesting that defects in these responses may be dependent on glucokinase-mediated glucose sensing.     

Does renal function deteriorate more rapidly in diabetic cardiac transplant recipients?

BACKGROUND: Selection criteria for cardiac transplant candidates with diabetes mellitus (DM) have been liberalized resulting in increased numbers of diabetic patients receiving organs. Calcineurin inhibition results in nephrotoxicity. Whether this nephrotoxicity is accelerated in diabetic heart transplant recipients is unknown. METHODS: To investigate this question, we derived the glomerular filtration rate (GFR) at transplant and at multiple time intervals thereafter for adult heart transplants performed from January 1, 2000 to January 1, 2005. GFR was estimated using the Modification of Diet in Renal Disease Study equation (GFRMDRD) and the Cockcroft-Gault (GFRCG) formula. RESULTS: In all, 257 patients were nondiabetic and 102 patients were diabetic before and after transplant. The diabetic patients were older (57+/-8 vs. 53+/-13 years; P<0.01) and had greater body mass index (27.5+/-5.1 vs. 25.5+/-4.4 kg/m; P<0.01) than nondiabetic patients. Baseline renal function was significantly reduced in diabetic patients with higher serum creatinine (1.6+/-0.5 vs. 1.4+/-0.5 mg/dL), lower GFRCG (65+/-27 vs. 73+/-35 mL/min), and lower GFRMDRD (54+/-23 vs. 65+/-32 mL/min; all P<0.01) than nondiabetic patients. All patients were treated with cyclosporine or tacrolimus posttransplant. The change in the GFRMDRD in nondiabetic and diabetic patients was constant and comparable at 1, 2, and 3 years posttransplant. In normal subjects, GFRMDRD declined from baseline by 7+/-26, 5+/-23, and 7+/-23 mL/min(2) and in the diabetic patients was 13+/-22, 9+/-26, 10+/-22 ml/min(2) at 1, 2, and 3 years, respectively (P=NS). CONCLUSION: This data suggests that nephrotoxicity posttransplant is not accelerated in diabetic recipients.     

Counterregulatory hormone and symptom responses to insulin-induced hypoglycemia in the postprandial state in humans

Plasma counterregulatory hormones and symptoms were measured during hypoglycemia in the postprandial and in the fasting state in humans to establish differences in physiological responses. We studied 8 nondiabetic subjects and 10 subjects with type 1 diabetes on two different occasions during clamped insulin-induced hypoglycemia (2.4 mmol/l) in the sitting position. On one occasion, subjects ate a standard mixed meal, and on the other they remained fasting. In response to postprandial as compared with fasting hypoglycemia, nondiabetic subjects exhibited lower total symptom scores (6.6 +/- 0.4 vs. 11.5 +/- 0.8, P = 0.001), which was due to less hunger (1.1 +/- 0.1 vs. 4.2 +/- 0.2), lower suppression of plasma C-peptide (0.23 +/- 0.1 vs. 0.08 +/- 0.07 nmol/l, P = 0.032), and greater responses of plasma glucagon (248 +/- 29 vs. 163 +/- 25 ng x l(-1) x min(-1), P = 0.018), plasma adrenaline (4.5 +/- 0.6 vs. 3.1 +/- 0.4 nmol x l(-1) x min(-1), P = 0.037), norepinephrine (3.8 +/- 0.3 vs. 3.2 +/- 0.2 nmol x l(-1) x min(-1), P = 0.037), and pancreatic polypeptide (217 +/- 12 vs. 159 +/- 22 pmol x l(-1) x min(-1), P = 0.08). Except for plasma C-peptide, responses in diabetic subjects were similarly affected. Notably, in diabetic subjects responses of glucagon, which were absent in the fasting state, nearly normalized after a meal. In conclusion, in the postprandial compared with the fasting hypoglycemic state, total symptoms are less, but counterregulatory hormones are greater and responses of glucagon nearly normalize in type 1 diabetic subjects.     

Impaired Proinsulin Processing is a Characteristic of Transplanted Islets

We sought to determine whether recipients of islet transplants have defective proinsulin processing. Individuals who had islet allo- or autotransplantation were compared to healthy nondiabetic subjects. Insulin (I), total proinsulin (TP), intact proinsulin and C-peptide (CP) were measured in samples of fasting serum by immunoassay, and the ratios of TP/TP+I and TP/CP were calculated. Islet allotransplant recipients had elevated TP levels relative to nondiabetic controls (16.8 [5.5–28.8] vs. 8.4 [4.0–21.8] pmol/L; p < 0.05) and autologous transplant recipients (7.3 [0.3–82.3] pmol/L; p < 0.05). Islet autotransplant recipients had significantly higher TP/TP+I ratios relative to nondiabetic controls (35.9 ± 6.4 vs. 13.9 ± 1.4%; p < 0.001). Islet allotransplant recipients, some of whom were on insulin, tended to have higher TP/TP+I ratios. The TP/CP ratio was significantly higher in both islet autotransplant (8.9 [0.6–105.2]; p < 0.05) and allotransplant recipients (2.4 [0.8–8.8]; p < 0.001) relative to nondiabetic controls (1.4 [0.5–2.6]%). Consistent with these findings, TP/TP+I and TP/CP values in islet autotransplant recipients increased significantly by 1-year posttransplant compared to preoperative levels (TP/CP: 3.8 ± 0.6 vs. 23.3 ± 7.9%; p < 0.05). Both allo- and autotransplant subjects who received <10 000 IE/kg had higher TP/CP ratios than those who received >10 000 IE/kg. Islet transplant recipients exhibit defects in the processing of proinsulin similar to that observed in subjects with type 2 diabetes manifest as higher levels of total proinsulin and increased TP/TP+I and TP/CP ratios.     

Results of our first nine intraportal islet allografts in type 1, insulin-dependent diabetic patients

With the first demonstration of insulin independence following intraportal islet transplantation into a patient with type 1 diabetes, a new era of clinical islet transplantation will begin. This report provides our initial experience of clinical islet transplantation with a total of nine consecutive portal vein islet transplants in seven diabetic recipients. The first three transplants were done in nonrenal failure diabetics (NRFI) using 6319 +/- 2173 islets/kg body weight with islets processed from single pancreas and cultured for 7 days at 24 degrees C. Prednisone, azathioprine, and cyclosporine were initiated prior to transplant. While all three recipients demonstrated C-peptide function posttransplant, all three rejected their grafts at 2 weeks. Five days of OKT3 treatment failed to recover more than 10% of their rejecting islet grafts. The studies were then shifted to established kidney transplant recipients (EKI) maintaining their basal immunosuppression while adding 7 days of Minnesota antilymphoblast globulin (MALG) to the recipient using islets from single donor pancreas that had been cultured for 7 days at 24 degrees C. There were an average of 6161 +/- 911 islets transplanted intraportally into three EKI recipients. All three had C-peptide response from the transplant, but none achieved insulin independence. While the first patient rejected his graft at 2 weeks, two recipients demonstrated long-term islet function up to 10 months posttransplant. Sustacal challenge testing demonstrated C-peptide responsiveness, but in a delayed pattern suggesting insufficient islet mass had been transplanted. The next three kidney transplant recipients received islets from more than one donor pancreas averaging 13,916 +/- 556 islets/kg body weight. The first of these was the first to achieve insulin independence from 10 to day 25 posttransplant when she appeared to have a rejection episode. The second and third recipients were retransplanted with islets from multiple donors having achieved partial islet function from single pancreas donor. The first patient on triple immunosuppression is demonstrating long-term partial function at 184 days but is not insulin independent. The third patient on prednisone and azathioprine received one half his islets after 7-day culture and the other half after 7-day culture combined with cryopreservation. He is continuing to demonstrate insulin independence for 154 days post-transplant with a glycated hemoglobin value of 5.6%. Sustacal challenge data demonstrate a total stimulated C-peptide response of 155 rhomol/ml at 4 months post-transplant compared with 148 +/- 12 rhomol/ml for normal controls (NC) and 425 rhomol/ml for nondiabetic, established kidney transplant recipients on triple immunosuppression.(ABSTRACT TRUNCATED AT 400 WORDS)     

Heart transplantation in mildly diabetic patients

From 1985 to 1989, 67 heart transplantations were performed in our hospital, 6 of them in non-insulin-dependent (type II) diabetic patients. Six pretransplantation type II diabetic male heart recipients (mean +/- SD age 50.0 +/- 7.3 yr) were compared with 61 nondiabetic recipients (mean age 44.5 +/- 11.0 yr; 55 men, 6 women) to define whether a different posttransplantation prognosis may be caused by pretransplantation diabetes. Before transplantation, all diabetic recipients (3 newly diagnosed and 3 with diabetes duration of 5, 6, and 12 yr, respectively) were in good glycemic control (mean fasting blood glucose 7.95 +/- 1.62 mM, mean HbA1c 7.6 +/- 0.2%). None had ocular or renal microangiopathic complications, 5 were treated only with diet, and 1 was treated with oral hypoglycemic agents. All recipients were treated with the same immunosuppressive protocol (cyclosporin, prednisone, and since 1986, azathioprine and antilymphocyte globulin), and mean dose and blood levels of cyclosporin were not significantly different between diabetic and nondiabetic recipients. After heart transplantation (mean follow-up 558 +/- 340 days in diabetic and 379 +/- 338 in nondiabetic recipients), the mortality rate and complications (i.e., rejection episodes, supplementary immunosuppressive treatments, major and minor infections, arterial hypertension, and graft atherosclerosis) showed no significant differences except for the more frequent arterial hypertension in diabetic recipients (P less than 0.05), although pretransplantation incidence of hypertension was lower in diabetic candidates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal compensation for impaired hepatic glucose release during hypoglycemia in type 2 diabetes: further evidence for hepatorenal reciprocity

During liver transplantation and after both meal ingestion and prolonged fasting, renal glucose release (RGR) increases while hepatic glucose release (HGR) decreases. These and other observations have led to the concept of hepatorenal reciprocity. According to this concept, reciprocal changes in hepatic and renal glucose release may occur to minimize deviations from normal glucose homeostasis. We further assessed this concept by testing the hypothesis that during counterregulation of hypoglycemia in patients with type 2 diabetes, who would be expected to have reduced HGR, RGR would be increased. Accordingly, we performed hypoglycemic hyperinsulinemic clamp experiments (approximately 3.1 mmol/l) in 12 type 2 diabetic and in 10 age-weight-matched nondiabetic volunteers and measured total endogenous glucose release (TEGR) and RGR using a combined isotopic net balance approach. HGR was calculated as the difference between TEGR and RGR since only these organs are capable of releasing glucose. We found that during comparable hypoglycemia and hyperinsulinemia, TEGR was reduced in type 2 diabetes (6.6 +/- 0.6 vs. 10.2 +/- 1.1 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.01) due to reduced HGR (3.9 +/- 0.5 vs. 8.6 +/- 1.0 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.0015). In contrast, RGR was increased approximately twofold in type 2 diabetes (3.3 +/- 0.5 vs. 1.6 +/- 0.3 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.015). Plasma epinephrine, lactate, and free fatty acid concentrations, which would promote RGR, were also greater in type 2 diabetes (all P < 0.01). Our results provide further support for hepatorenal reciprocity and may explain at least in part the relatively low occurrence of severe hypoglycemia in type 2 diabetes compared with type 1 diabetes where both HGR and RGR counterregulatory responses are reduced.     

Reduced progression of diabetic retinopathy after islet cell transplantation compared with intensive medical therapy

BACKGROUND: Diabetic retinopathy is a major complication of type 1 diabetes and remains a leading cause of visual loss. There have been no comparisons of the effectiveness of intensive medical therapy and islet cell transplantation on preventing progression of diabetic retinopathy. METHODS: The British Columbia islet transplant program is conducting a prospective, crossover study comparing medical therapy and islet cell transplantation on the progression of diabetic retinopathy. Progression was defined as the need for laser treatment or a one step worsening along the international disease severity scale. An interim data analysis was performed after a mean 36-month follow-up postislet transplantation and these results are presented. RESULTS: The medical and postislet transplant groups were similar at baseline. Subjects after islet transplantation had better glucose control than the medically treated subjects (mean HbA1c 6.7%+/-0.9% vs. 7.5+/-1.2, P<0.01) and were C-peptide positive. Progression occurred significantly more often in all subjects in the medical group (10/82 eyes, 12.2%) than after islet transplantation (0/51 eyes, 0%) (P<0.01). Considering only subjects who have received transplants, progression occurred in 6/51 eyes while on medical treatment and 0/51 posttransplant (P<0.02). CONCLUSIONS: Progression of diabetic retinopathy was more likely to occur during medical therapy than after islet cell transplantation.