Metabolic follow-up after long-term pancreas graft survival

DESIGN: Successful pancreas transplantation results in insulin independence and normoglycemia. This prospective study was performed to investigate long-term metabolic changes after pancreas transplantation. METHODS: Thirty-eight type 1 diabetic patients after simultaneous pancreas/kidney transplantation (SPK) with a pancreas graft survival for at least 10 years were studied in a prospective manner. HbA(1c) and glucose levels before and during an oral glucose tolerance test (OGTT) were analyzed from 3 months to 10 years after SPK. In addition, insulin secretion and glucagon response were measured. RESULTS: Fasting glucose increased slightly and continuously from 3 months to 10 years (from 78 +/- 3 to 91 +/- 2 mg/dl). Even HbA(1c) levels showed a mild but significant increase from 3 months to 10 years after SPK. Glucose tolerance deteriorated markedly 10 years after SPK. Insulin secretion during OGTT remained stable for 10 years. Parameters of insulin resistance and sensitivity did not change significantly but glucagon secretion increased significantly during the course after SPK. Late after SPK, glucagon levels were higher in patients with an impaired or diabetic glucose tolerance. CONCLUSIONS: Pancreas transplantation is able to restore endogenous insulin secretion for 10 years or more. Especially, late after SPK, a deterioration of glycemic control was detected, even if glucose values were within the normal range. During prospective long-term follow-up, an increase of glucagon secretion but no decrease of insulin secretion was detected.     

Sequential metabolic studies of pancreas allograft function in type 1 diabetic recipients.

We have previously shown that the loss of acute first phase insulin secretion precedes pancreas allograft rejection and development of glucose intolerance in Type 1 diabetic patients. In order to examine whether there is a progressive loss of phases of insulin secretion and beta-cell function in technically successful pancreas transplants during the first year, we measured glucose, insulin, and C-peptide responses to physiological (mixed meal) and pharmacological (IV glucose and IV glucagon) stimulation in 27 glucose-tolerant, insulin-independent allograft recipients at 3, 6, and 12 months. Mean +/- SE fasting serum glucose levels were normalized throughout the study period. Postprandial serum glucose profiles tended to increase by 12 months compared to 3 and 6 months, although peak glucose levels were not statistically different. Following pancreas transplantation, basal serum insulin levels were high at 3 months (163 +/- 17 pM), 6 months (165 +/- 22 pM), and 12 months (248 +/- 54 pM, p = NS) in the Type 1 diabetic pancreas allograft recipients when compared to normal (25 +/- 3 pM). We observed slight elevations in postprandial insulin and C-peptide profiles at 12 months compared to 3 and 6 months. Following IV glucose and glucagon stimulation, serum insulin and C-peptide levels as well as phases of insulin release did not differ over the 12-month study period. Similarly, the glucose decay constant (KG) was nearly identical at 3, 6, and 12 months. In summary, 1 year following successful whole cadaveric, heterotopic pancreas transplantation in Type 1 diabetic recipients, fasting serum glucose remains normalized, while postprandial glucose tends to rise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation.

Cirrhosis is often associated with insulin resistance and glucose intolerance. We evaluated if these alterations are restored by liver transplantation (LT). Glucose tolerance (oral glucose tolerance test [OGTT]), peripheral insulin sensitivity (euglycemic insulin clamp technique), glucose oxidation (indirect calorimetry), nonoxidative glucose disposal, and insulin secretion (hyperglycemic clamp technique) were measured in 6 patients (Group 1) before and 6 months after LT, in 12 patients (Group 2) who underwent LT 6 to 30 months previously, and in 6 healthy individuals (controls). In Group 1, glucose tolerance and insulin sensitivity (3.24 +/- 0.37 mg/kg/min) were normalized after LT (8.6 +/- 0.77 mg/kg/min; P <.0001; P = not significant vs. controls). The improved insulin-mediated glucose uptake was the result of a normalization of nonoxidative glucose disposal. Fasting insulin and C-peptide decreased from 24.6 +/- 3.3 microU/mL and 4.37 +/- 0.46 ng/dL, respectively, to 12.7 +/- 1.9 microU/mL and 2.46 +/- 0.5 ng/dL (controls: 10.0 +/- 3 microU/mL and 1.45 +/- 0.34 ng/dL). The glucose-induced increase of insulin concentration, which was higher before LT, showed a significant reduction, although the first phase of beta-cell secretion remained significantly higher compared with that of controls. All these findings were also confirmed in Group 2. The present data indicate that LT normalizes glucose tolerance and insulin sensitivity in cirrhotic patients through an improvement of both hepatic glucose clearance and the peripheral glucose disposal. The latter effect may be the result of the correction of chronic hyperinsulinemia. An increased first-phase beta-cell insulin secretion in response to high glucose levels persists, suggesting that a memory of previous insulin resistance is maintained.     

Idiopathic reactive hypoglycemia: a role for glucagon?

We previously reported that patients with idiopathic reactive hypoglycemia (plasma glucose concentration lower than 2.5 mmol/L 2-4 h after the ingestion of 75 g of glucose) display reduced or absent counterregulatory response of the glucagon secretion and increased insulin sensitivity. In order to examine the effect of glucagon on the increased insulin sensitivity in these patients, 12 subjects with idiopathic reactive hypoglycemia underwent a two-step hyperinsulinemic (1 mU/kg.min) euglycemic glucose clamp and were compared with 12 normal control subjects matched for age, weight and sex. During the first step of the glucose clamp (only insulin + glucose infusion) the patients with Idiopathic Reactive Hypoglycemia required higher glucose infusion rates to maintain euglycemia than normal subjects (9.09 +/- 0.29 mg/kg. min vs 7.61 mg/kg.min). When basal glucagon secretion was replaced (+ somatostatin and glucagon, second step of the clamp) the glucose infusion rates required to maintain euglycemia in patients with Idiopathic Reactive Hypoglycemia significantly decreased (to 7.17 +/- 0.40 mg/kg.min) and resulted similar to normal subjects (7.64 +/- 0.41 mg/kg.min). Thus, in patients affected by Idiopathic Reactive Hypoglycemia, glucagon secretion may play an important role in the pathogenesis of the increased insulin sensitivity and hypoglycemia.     

Impaired glucose tolerance in pancreas grafted diabetic patients is due to insulin secretory defects.

INTRODUCTION: Pancreas transplantation in diabetic patients can sustain insulin independence for years. The aim of the study was to measure the incidence of an impaired or diabetic glucose tolerance in patients after successful transplantation and analyse insulin resistance and insulin secretion. METHODS: 174 Type 1 diabetic recipients of simultaneous pancreas/kidney (SPK) transplants were investigated early (three months) and 95 patients late (five years) after transplantation using an oral glucose tolerance test combined with an iv arginine load. RESULTS: Although mean fasting blood glucose and HbA1c levels were within the normal range, only 65% of the patients displayed a normal glucose tolerance (NGT), whereas 25% had an impaired (IGT) and 10% showed a diabetic glucose tolerance (DGT). Fasting blood glucose and HbA1c values were significantly lower in patients with NGT compared to graft recipients with IGT or DGT, either three months or five years after SPK. Indicators of insulin resistance (fasting insulin, HOMA-IR, Matsuda/de Fronzo Index) were elevated in all graft recipients, but no differences were found between groups. In contrast insulin secretion was significantly reduced in patients with IGT and DGT early and late after transplantation. SUMMARY: Insulin resistance is a common feature after pancreas transplantation. However, either three months or five years after SPK abnormal glucose tolerance was mainly due to a reduced glucose- and arginine-induced secretory response of insulin.     

Effects of the new oral hypoglycaemic agent nateglinide on insulin secretion in Type 2 diabetes mellitus.

AIMS: The new non-sulphonylurea oral hypoglycaemic agent nateglinide has been shown to enhance insulin secretion in animals and in healthy human volunteers and thus offers a potential advance in the treatment of Type 2 diabetes mellitus. This study examined whether nateglinide can enhance insulin secretion, and particularly the first phase insulin response, in patients with Type 2 diabetes. METHODS: A double-blind, placebo-controlled trial, examining the effects of a single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0-44 months). RESULTS: Insulin secretion (both overall and first phase) was significantly increased by nateglinide (P < 0.001), as were C-peptide (P < 0.001) and proinsulin (P < 0.001) secretion. Overall glucose concentrations following glucose challenge were lower after nateglinide than after placebo (P = 0.05). CONCLUSIONS: Nateglinide significantly increases insulin secretion in Type 2 diabetic patients, in particular restoring the first phase insulin response. Further study is necessary to determine the effects of chronic administration on insulin secretion and blood glucose concentration.     

Repaglinide treatment amplifies first-phase insulin secretion and high-frequency pulsatile insulin release in Type 2 diabetes.

AIMS/HYPOTHESIS: First-phase insulin release and coordinated insulin pulsatility are disturbed in Type 2 diabetes. The present study was undertaken to explore a possible influence of the oral prandial glucose regulator, repaglinide, on first-phase insulin secretion and high-frequency insulin pulsatility in Type 2 diabetes. METHODS: We examined 10 patients with Type 2 diabetes in a double-blind placebo-controlled, cross-over design. The participants were treated for 6 weeks with either repaglinide [2-9 mg/day (average 5.9 mg)] or placebo in random order. At the end of each treatment period, first-phase insulin secretion was measured. Entrainment of insulin secretion was assessed utilizing 1-min glucose bolus exposure (6 mg/kg body weight every 10 min) for 60 min during (A) baseline conditions, i.e. 12 h after the last repaglinide/placebo administration, and (B) 30 min after an oral dose of 0.5 mg repaglinide/placebo with subsequent application of time-series analyses. RESULTS: Postprandial (2-h) blood glucose was significantly reduced by repaglinide after 5 weeks of treatment (P < 0.001). The fall in HbA(1c) did not reach statistical significance (P = 0.07). AUC(ins,0-12 min) during the first-phase insulin secretion test was enhanced (P < 0.05). In addition, glucose entrained insulin secretory burst mass and amplitude increased markedly (burst mass: repaglinide, 44.4 +/- 6.0 pmol/l/pulse vs. placebo, 31.4 +/- 3.3 pmol/l/pulse, P < 0.05; burst amplitude: repaglinide, 17.7 +/- 2.4 pmol/l/min vs. placebo, 12.6 +/- 1.3 pmol/l/min, P < 0.05) while basal insulin (non-pulsatile) secretion was unaltered. After acute repaglinide exposure (0.5 mg) basal insulin secretion increased significantly (P < 0.05). Neither acute nor chronic repaglinide administration influenced frequency or regularity of insulin pulses during entrainment. CONCLUSION/INTERPRETATION: Repaglinide augments first-phase insulin secretion as well as high-frequency insulin secretory burst mass and amplitude during glucose entrainment in patients with Type 2 diabetes, while regularity of the insulin release process was unaltered.     

The effect of manipulation of basal pulsatile insulin on insulin action in Type 2 diabetes.

AIM: Disordered insulin pulsatility is associated with insulin resistant states including Type 2 diabetes. However, whether abnormal basal insulin pulses play a role in the pathogenesis of insulin resistance or are simply an associated feature remains undetermined. We investigated this relationship further by studying the effect of overnight (10 h) pulsatile insulin infusion on subsequent insulin sensitivity. METHODS: We studied 17 Type 2 diabetic patients who underwent one of two protocols. In protocol A (10 patients) on two separate nights we infused insulin 0.1 mU/kg/min either in a constant infusion or in pulses every 13 min. Octreotide (0.43 microg/kg/h) was given to suppress endogenous insulin secretion and physiological replacement of glucagon (30 ng/kg/h) administered. Insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp (2 mU/kg/min) next morning. In protocol B (seven patients), we employed the same experimental procedure but used a basal insulin infusion rate of 0.09 mU/kg/min in 7-min or 13-min pulses. RESULTS: Appropriate pulse patterns were confirmed in each protocol. In protocol A, after overnight infusions, glucose infusion rates required to maintain euglycaemia at steady state hyperinsulinaemia were similar (33.9 +/- 5.2 vs. 31.2 +/- 4.1 micromol/kg/min; P = NS). In protocol B, after overnight infusions the glucose infusion rates required during hyperinsulinaemia were significantly lower during 7-min pulses (39.9 +/- 5.7 vs. 44.7 +/- 5.6 micromol/kg/min; P < 0.05). CONCLUSION: There was no demonstrable priming effect derived from overnight pulsatile insulin compared with constant insulin infusion on subsequent insulin sensitivity in Type 2 diabetic subjects. The failure of 7-min pulses to exhibit an advantageous effect over 13-min pulses raises questions about the natural frequency of basal insulin pulses and their biological effect.     

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects.

AIMS: Hepatic glycogen stores have been shown to be depleted, and glucagon stimulated hepatic glucose production reduced, in Type 1 diabetic subjects. Co-administration of amylin and insulin has been shown to replete hepatic glycogen stores in diabetic animal models. The aim of the present study was to investigate the effect of amylin replacement on hepatic glucagon responsiveness in humans. METHODS: Thirteen Type 1 diabetic men were studied in a double-blind, placebo-controlled, cross-over study after 4 weeks of subcutaneous pramlintide (30 microg q.i.d.) or placebo administration. Following an overnight fast, plasma glucose was kept above 5 mmol/l (baseline 210-240 min) with an insulin infusion rate of 0.25 mU x kg(-1) x min(-1). To control portal glucagon levels, somatostatin was infused at a rate of 200 microg/h. Basal growth hormone (2 ng x kg(-1) x min(-1)) and glucagon (0.7 ng x kg(-1) x min(-1)) were replaced. Glucagon infusion was increased to 2.1 ng x kg(-1) x min(-1) at 240-360 min (step 1) and to 4.2 ng x kg(-1) x min(-1) at 360-420 min (step 2). RESULTS: Baseline plasma glucose (5.59+/-0.16 vs. 5.67+/-0.25 mmol/l) and endogenous glucose production (EGP) (1.32+/-0.22 vs. 1.20+/-0.13 mg x kg(-1). min(-1)) were similar and the response to glucagon was unaffected by pramlintide (glucose: step 1; 6.01+/-0.31 vs. 5.94+/-0.38 mmol/l, step 2; 6.00+/-0.37 vs. 5.96+/-0.50 mmol/l, EGP: step 1; 1.91+/-0.18 vs. 1.83+/-0.15 mg x kg(-1) x min(-1), step 2; 2.08+/-0.17 vs. 1.96+/-0.16 ng x kg(-1) x min(-1), pramlintide vs. placebo). Glucose disposal rates were similar at baseline (2.44+/-0.13 vs. 2.28+/-0.09 mg x kg(-1) x min(-1), pramlintide vs. placebo) as well as during the glucagon challenge (P-values all > 0.2). CONCLUSIONS: Co-administration of pramlintide and insulin to Type 1 diabetic subjects for 4 weeks does not change the plasma glucose or endogenous glucose production response to a glucagon challenge, following an overnight fast. In addition, pramlintide administration does not appear to alter insulin-mediated glucose disposal.     

Insulin sensitivity during oral glucose tolerance test and its relations to parameters of glucose metabolism and endothelial function in type 2 diabetic subjects under metformin and thiazolidinedione

AIM: This study was designed to assess the usefulness of a model-based index of insulin sensitivity during an oral glucose tolerance test (OGTT) in the identification of possible changes in this metabolic parameter produced by pharmacological agents known to be potent insulin sensitizers, that is metformin (M) and thiazolidinedione (T). The association of these agents with several other factors related to glucose metabolism was also investigated, as well as the relation of insulin sensitivity and secretion with markers of endothelial function such as different adhesion molecules (cAMs), that is vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-Selectin. METHODS: Twenty type 2 diabetic patients treated with diet only underwent a 3-h OGTT for measurement of plasma glucose, insulin, proinsulin, C-peptide and cAMs before and after administration of randomly given M (n = 9; 1700 mg/day) or T (n = 11; 600 mg/day). After 16 weeks of treatment, a second OGTT was performed. Insulin sensitivity was calculated with homeostasis model assessment and with oral glucose insulin sensitivity (OGIS), which quantifies dynamic glucose clearance per unit change of insulin. Insulin secretion was assessed by modelling technique. Differences in these parameters before and after treatment, as well as possible relationships with cAMs, were assessed. RESULTS: Basal and stimulated plasma glucose decreased after therapy in both the groups by approximately 20%. Basal insulin resistance also decreased. Insulin sensitivity in dynamic conditions (OGIS: ml/min/m(2)) increased with M (289.3 +/- 18.8 vs. 234.7 +/- 18.1, p < 0.02) and tended to improve with T (323.5 +/- 18.1 vs. 286.8 +/- 22.1, p = 0.09). Total insulin secretion over the OGTT [TIS: nmol/l(3 h)] tended to decrease with M (17.1 +/- 2.5 vs. 27.3 +/- 0.3, p = 0.08) but not with T (23.6 +/- 3.5 vs. 22.5 +/- 2.7). Plasma concentrations of E-Selectin decreased in T (38.0 +/- 2.3 vs. 51.2 +/- 6.1 ng/ml, p < 0.05). No correlation was found between insulin sensitivity and cAMs. CONCLUSIONS: Model-based indices of insulin sensitivity and secretion during an OGTT can be able to detect changes observed in patients under treatment with pharmacological agents such as M or T. Both the drugs improved glucose control similarly. Decreased plasma E-Selectin concentrations were seen in patients on T therapy only.     

The insulin secretagogues glibenclamide and repaglinide do not influence growth hormone secretion in humans but stimulate glucagon secretion during profound insulin deficiency

In vitro data have recently suggested that sulfonylureas (SUs) enhance GH secretion by modulating the effects of GHRH and somatostatin in pituitary cells. The present study was undertaken to explore in more detail a possible influence of a single dose of SU (glibenclamide) and a non-SU (repaglinide) insulin secretagogue on circulating GH dynamics. Ten C-peptide-negative type 1 diabetic individuals were examined on three occasions in random order. Either glibenclamide (10.5 mg), repaglinide (8 mg), or placebo was administered after overnight normalization of plasma glucose by iv insulin infusion. Subsequently, GH concentrations were measured regularly after stimulation with GHRH (bolus 0.1 micro g/kg) alone and during concomitant infusion with somatostatin (7 ng.kg(-1).min(-1)). Insulin was replaced at baseline levels (0.25 mU.kg(-1).min(-1)) and plasma glucose clamped at 5-6 mmol/liter. Overall, there were no significant statistical differences in GH responses determined as either GH peak concentrations, integrated levels of GH, or secretory burst mass of GH during the experimental protocol. In contrast, plasma glucagon concentrations were significantly increased during glibenclamide and repaglinide exposure. The present experimental design does not support the hypothesis that acute administration of pharmacological doses of the oral antihyperglycemic agents glibenclamide and repaglinide per se enhance GH release in humans. Additionally, this study shows that these potassium channel inhibitors seem to stimulate glucagon secretion in people who have severe intraislet insulin deficiency (e.g. type 1 diabetes). However, extrapolation of our findings to type 2 diabetic individuals should be done with some caution.     

Effects of long term sulfonylurea therapy on plasma insulin and fasting lipid levels.

Insulin secretion was studied before and after the control of hyperglycemia in fourteen maturity onset male non-obese diabetics. Optimum control of hyperglycemia was achieved by the addition of the sulfonylurea chlorpropamide to dietary treatment. One patient was a primary treatment failure, but nine out of thirteen had excellent control of hyperglycemia. A standardized oral glucose tolerance test (GTT) was performed before and after eight months of individualized therapy with the sulfonylurea. The GTT was repeated with each patient taking his usual dose of chlorpropamide 90 min prior to the administrationo f the glucose load. In the baseline test glucose levels rose from 135.6 +/- 9.9 mg/dl to a peak level of 268.8 +/- 17.7 mg/dl at 120 min. After control of hyperglycemia glucose levels were significantly lower at 0, 30 and 60 min, and rose from 106.8 +/- 8.5 mg/dl to a maximum of 224.5 +/- 17.3 mg/dl at 120 min. Plasma insulin response was unchanged. Fasting serum cholesterol, triglyceride and total lipid levels changed only minimally during therapy. It is concluded that lowered serum glucose levels after long term treatment with chlorpropamide occured while plasma insulin response to glucose was no greater than before treatment. These findings may be explained by an extrapancreatic effect of the drug or by an indirect result of chlorpropamide induced insulin release which occured earlier in the course of therapy.     

Pancreatic endocrine function in cirrhotic rats

Pancreatic endocrine function in liver cirrhosis was examined in rats both in vivo and in vitro. Experimental liver cirrhosis was induced by subcutaneous injections of 50% carbon tetrachloride in a dose of 2 mL/kg body weight twice a week for 16 weeks. Control rats received a similar dose of olive oil during the same period. In cirrhotic rats, immunoreactive insulin contents in the pancreas were significantly lower, whereas immunoreactive glucagon contents were about threefold higher than those of control rats. In the first part of this study, insulin and glucagon concentrations in both jugular and portal venous blood at basal conditions and after oral glucose loading were simultaneously determined in vivo. Peripheral insulin levels, both before and after glucose loading, were higher, whereas portal insulin concentrations were lower in cirrhotic rats than in the control rats. In contrast, glucagon levels in both the peripheral and portal veins were significantly higher in cirrhotic rats than in control rats. In the second part, isolated perfused pancreata were prepared from cirrhotic and control rats to further characterize the endocrine function of cirrhotic rat pancreas. Insulin secretion in response to 16.7 mmol/L glucose and 100 pmol/L cholecystokinin-octapeptide both were 40% lower in cirrhotic rats than in controls. In contrast, there was no significant difference in arginine-stimulated insulin release between the two groups. However, glucagon secretion in response to 20 mmol/L arginine was 40% higher in cirrhotic rats. If sensitivity is defined as the hormone release proportional to the pancreatic contents, then A and B cells in the cirrhotic rats had normal sensitivity to both glucose and cholecystokinin-octapeptide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glipizide treatment of pancreas autotransplantation: effects on alterations in glucose-insulin relationships.

Pancreas transplantation has been proven effective in supplying an endogenous insulin supply in diabetics. However, alterations in glucose metabolism after transplantation suggest a possible "insensitivity" to its action in the periphery. We hypothesized that sulfonylurea treatment of canines who had received segmental pancreas autotransplants would correct these alterations by altering peripheral insulin sensitivity. Glipizide therapy (5 mg p.o. b.i.d.) did appear, in fact, to enhance basal insulin sensitivity by lowering fasting glucose (100 +/- 3 to 81 +/- 11 mg/dl pre-treatment to post-treatment) while not affecting basal insulin levels. However, glipizide therapy was associated with decreased insulin response to challenge by either oral glucose (2 gm/kg) or sustained intravenous hyperglycemia (150 mg/dl above basal). We conclude that our model of pancreas autotransplantation documents alterations in glucose metabolism which are devoid of the effect of immunosuppression. Glipizide treatment appears to affect fasting sensitivity to insulin, but results in a decrement of insulin response to oral or intravenous glucose challenge.     

Oestradiol replacement treatment and glucose homeostasis in two men with congenital aromatase deficiency: evidence for a role of oestradiol and sex steroids imbalance on insulin sensitivity in men.

AIMS: The role of sex steroids in glucose and insulin metabolism in men remains unclear. To investigate the effects of sex steroids and oestrogen on insulin sensitivity in men, we studied two male adults with aromatase deficiency (subject 1 and subject 2). METHODS: The effects of transdermal oestradiol (tE(2)) treatment at different dosages on insulin sensitivity were studied before tE(2) treatment (phase 1), and after 6 months (phase 2) and 12 months of tE(2) treatment (phase 3) by means of homeostasis model assessment-insulin resistance (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI), insulin tolerance test (ITT), and oral glucose tolerance test (OGTT). The latter was performed only in subject 1, as subject 2 suffered from Type 2 diabetes. RESULTS: The restoration of normal serum oestradiol led to improved insulin sensitivity, as shown by changes in HOMA-IR and QUICKI. The ITT provided evidence of improved insulin sensitivity during tE(2) treatment. Insulin secretion after OGTT was reduced during tE(2) treatment in subject 1. After 12 months of tE(2) treatment, insulin sensitivity was improved compared with in phases 1 and 2. CONCLUSIONS: The study suggests a direct involvement of oestrogens in insulin sensitivity, and supports a possible role of oestradiol : testosterone ratio, which may be as influencial as the separate actions of each sex steroid on glucose homeostasis.     

Metabolic consequences of pancreatic systemic or portal venous drainage in simultaneous pancreas-kidney transplant recipients.

AIMS: The aim was to investigate pancreatic B-cell function and insulin sensitivity in simultaneous pancreas-kidney (SPK) recipients with systemic or portal venous drained pancreas allograft using simple and easy tests. METHODS: The study included 44 patients with Type 1 diabetes and end-stage renal disease who had undergone SPK transplantation: 20 recipients received a pancreas allograft with systemic venous drainage (S-SPK) and 24 with portal venous drainage (P-SPK). We studied only recipients with functioning grafts, with normal serum glucose, HbA(1c) and serum creatinine values, on a stable drug regimen. The subjects were studied at 6, 12, 24, 36, 48 and 60 months after transplantation. Insulin sensitivity and B-cell function indices were derived from blood samples and oral glucose tolerance tests. RESULTS: All patients from both groups had normal fasting glucose, body mass index and HbA(1c) values by selection. The homeostatic model (HOMA) beta-cell index was significantly lower in P-SPK recipients at several points of the follow-up. HOMA-IR was significantly higher in S-SPK recipients at 6 and 24 months after transplantation and was positively correlated with fasting insulin values, but never exceeded 3.2. There was no significant difference in QUICKI index values between the two groups. Although all patients from both groups always had normal glucose tolerance, the area under the insulin curve was higher in the S-SPK group. Cholesterol, low-density lipoprotein-cholesterol and triglycerides were higher in the P-SPK group. CONCLUSIONS: The results suggest sustained long-term endocrine function in both groups and show that portal venous drainage does not offer major metabolic advantages.     

Beta-cell dysfunction and low insulin clearance in insulin-resistant human immunodeficiency virus (HIV)-infected patients with lipodystrophy

OBJECTIVE: To obtain a better understanding of the physiological aspects of glucose homeostasis in human immunodeficiency virus (HIV)-infected patients with lipodystrophy, we evaluated separately beta-cell function and insulin sensitivity after an oral glucose load. DESIGN: Beta-cell function was investigated during an oral glucose tolerance test (OGTT) (75 g, 180 min) in 16 lipodystrophic HIV-infected patients and in 15 age- and weight-matched nonlipodystrophic HIV-infected patients. All participants were sedentary Caucasian males, who were on highly active antiretroviral therapy with no history of diabetes mellitus or impaired glucose tolerance. Prehepatic insulin secretion rates were estimated by deconvolution of C-peptide concentrations. A composite measure of insulin sensitivity was derived from the OGTT. RESULTS: Beta-cell secretory capacity (i.e. the rate of change in insulin secretion per unit change in glucose concentration) was similar in lipodystrophic and nonlipodystrophic patients (6.2 +/- 1.0 mU kg(-1) min(-1) mg(-1) dl vs. 5.4 +/- 0.4, P > 0.4), but insulin sensitivity was reduced by 61% in lipodystrophic patients (P < 0.004). The disposition index (insulin capacity multiplied with insulin sensitivity) and insulin clearance rate were reduced in lipodystrophic patients (-55%, P < 0.003 and -31%, P < 0.004). Insulin clearance rate correlated strongly with insulin sensitivity (r = 0.82, P < 0.001). More lipodystrophic than nonlipodystrophic patients exhibited impaired glucose tolerance and diabetes mellitus (63%vs. 20%, P < 0.05). CONCLUSIONS: Our data support the concept that impaired glucose tolerance in lipodystrophic HIV-infected patients relates to a failure of the beta-cells to fully compensate for decrements in insulin sensitivity despite simultaneous reduction in insulin clearance.     

Combination of continuous subcutaneous infusion of insulin and octreotide in Type 1 diabetic patients

The effect of 7 day continuous subcutaneous infusion of octreotide (200 microg day(-1)) was evaluated in seven insulin-pump treated Type 1 diabetic patients (age 43+/-1.5 year; BMI 25.1+/-0.7 kg m(-2); HbA(1c) 7.4+/-0.3%). A 24-h metabolic and hormonal profile, and a euglycaemic hyperinsulinaemic clamp (0.25, 0.5, 1.0 mg kg(-1) min(-1)), with [3H]glucose infusion and indirect calorimetry, were performed before and after a 7-day octreotide infusion. Mean 24-h plasma glucose was similar before and after octreotide (9.7+/-0.8 vs. 9.1+/-1.0 mmol l(-1)) but insulin requirement dropped by 45% (49+/-4 vs. 27+/-2 U day(-1); P<0.01). Both 24-h plasma hGH and glucagon were suppressed by octreotide (1.85+/-0.35 vs. 0.52+/-0.04 microg l(-1), and 117+/-23 vs. 102+/-14 ng l(-1), respectively). Glucose utilisation increased after octreotide (insulin 0.5 mU kg(-1) min(-1) clamp 3.09+/-0.23 vs. 4.19+/-0.19 mg kg(-1) min(-1); 1 mU kg(-1) min(-1) clamp 5.64+/-0.61 vs. 7.93+/-0.57 mg kg(-1) min(-1); both P<0.05) and endogenous glucose production was similarly suppressed. Glucose oxidation was not affected by octreotide, while the improvement in glucose storage (insulin 1.0 mU kg(-1) min(-1) clamp 3.89+/-0.60 vs. 5.64+/-0.67 mg kg(-1) min(-1), P<0.05) entirely accounted for the increase in glucose disposal. Endogenous glucose production was more effectively suppressed at the two lower insulin infusion rates (P>0.05). Energy expenditure declined after octreotide. Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose metabolism by enhancing glucose storage, and reduces energy expenditure. These results support a role for counterregulatory hormones in the genesis of insulin resistance and the catabolic state of Type 1 diabetes.