The use of the artificial pancreas in uremic diabetic patients.

Maintenance hemodialysis and renal transplantation are increasingly used for treating diabetic patients with end-stage renal failure. The use of the artificial pancreas is able to prevent large blood glucose fluctuations in these patients with atherosclerosis, advanced retinopathy or neuropathy in which hyper- and hypoglycemia are potentially deleterious. For this purpose, we have developed and are utilizing an artificial pancreas easily utilizable without special training by the staff of a dialysis unit. This artificial pancreas uses a polarographic glucose electrode with a fast response time (45 to 90 seconds), a terminal display for operator communication, and a continuous digital and analogyl display for control of the running operation. There is also a printer to display in tabular and graphical form the values at any time during the operation. In this preliminary study, 7 patients have been studied: five under repetitive hemodialysis for four hours, 3 times a week; one treated by peritoneal dialysis for 12 hours, twice a week and one controlled during, and 48 hours after, renal transplantation. The macroscopic pancreas normalizes blood glucose under these circumstances, helps in a better understanding of blood glucose homeostasis in uremic patients under dialysis, leads to a more precise evaluation of insulin needs, may help to improve the nutritional status of the patients, and has an educational value for the patient and the medical staff.     

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Several previous studies have shown that renal failure decreases not only renal elimination but also metabolic clearance of drugs, particularly those metabolized by CYP3A. However, whether recovery of renal function results in recovery of hepatic CYP3A activity remains unknown. In this study, we evaluated the effect of renal function on CYP3A activity after kidney transplantation in patients with end-stage renal disease (ESRD) by measuring the change in CYP3A activity using plasma concentration of 4β-hydroxycholesterol as a biomarker. The study enrolled 13 patients with ESRD who underwent the first kidney allograft transplantation. Morning blood samples were collected before and 3, 7, 10, 14, 21, 30, 60, 90, 120, 150 and 180 days after kidney transplantation. Plasma concentration of 4β-hydroxycholesterol was measured using GC-MS. Compared with before kidney transplantation, creatinine clearance increased significantly from day 3 after kidney transplantation and stabilized thereafter. Plasma concentration of 4β-hydroxycholesterol was elevated significantly on days 90 and 180 after kidney transplantation. In conclusion, this study suggests the recovery of CYP3A activity with improvement in renal function after kidney transplantation in patients with ESRD.     

From Langerhans Islets to Pancreas Transplantation over the past 30 years: A Review with Personal Contributions

Organ, tissue and cell banking is currently an important method used to prevent death of cells in replacement transplantation therapy. From 1975 to 1985 the author performed experimental transplantations of islets isolated by collagenase digestion through injection into the liver through the portal vein, or by transplantation of minced neonatal pancreases under the renal capsule of alloxan or spreptozotocin into severely chronic diabetic rats and mice. Seventy of the 256 transplanted rats and mice were cured for 1 year, i.e. one-third of their life span, at the 3rd to 15th inbreeding and only 2 weeks of immunosuppression by azathioprine or cyclosporin A. The author compares his results with those achieved later with diabetic patients by whole pancreas transplantation, including prevention of diabetic renal and ocular complications, infertility, health of progeny of cured rats, and slow rejection and possibility of cure by repeated transplantation. He welcomes the return to islet transplantation, and possibly also of immunologically tolerant pancreatic stem cell transplantation, or transplantation of subcutaneous fibroblasts, transfected with a complex insulin gene, which will produce adequate insulin to prevent hyperglycemia, as does hepatic pyruvate kinase from an insulin analog, a therapy that will not need permanent immunosuppression.     

Pancreatic duct occlusion with Ethibloc. An experimental study in juvenile pigs

In the transplantation of vascularized pancreatic grafts severe problems are related to the exocclusion is an improved alternative to duct ligation in producing atrophy of the exocrine pancreas while leaving the endocrine pancreas intact. Fractional growth rate in duct-ligated and duct-occluded animals was reduced to 1/3 - 1/4 of that of sham operated controls. Fasting blood glucose, fasting insulin, sum of blood glucose and glucose elimination rate during an intravenous glucose tolerance test remained normal in the duct-ligated and Ethibloc-occluded animals. There was a diminished insulin response to a maximal glucose load. In spite of this, the glucose tolerance remained virtually normal. The volume of the pancreas was reduced to 1/3 of its normal size after both experimental procedures. Histologically, the islets appeared to remain normal, while the exocrine portion of the gland was replaced by fibrous tissue. No traces of the active compound, Ethibloc, remained after 4 weeks. This study shows that pancreatic duct occlusion with Ethibloc results in impairment of endocrine function. Consequently, Ethibloc duct occlusion does not seem to be a superior alternative to other methods of producing exocrine atrophy in organs intended for transplantation.     

Circulating adrenomedullin is increased in relation with increased creatinine and atrial natriuretic peptide in liver-transplant recipients

OBJECTIVES: Circulating adrenomedullin (ADM), a potent vasorelaxing and natriuretic peptide involved in cardiovascular homeostasis, is increased after cardiac and renal transplantation. ADM is also implicated in hemodynamic abnormalities during liver cirrhosis, but whether ADM is increased late after liver transplantation is unknown. PATIENTS: A total of 18 subjects--10 liver-transplant patients (Ltx) and 8 healthy subjects--were enrolled in the study. DESIGN AND MEASUREMENTS: After a 15-min rest period in supine position, heart rate and systemic blood pressure were determined in all subjects. Then, venous blood samples were obtained in order to simultaneously determine the cyclosporine through levels, the biological (cyclosporine, renal and hepatic functions) and hormonal (ADM and atrial natriuretic peptide (ANP)) characteristics of the Ltx. RESULTS: ADM (27.2+/-4.1 vs. 53.8+/-6.9 pmol/l, P=0.02), and ANP (5.9+/-0.9 vs. 12.8+/-1.4 pmol/l, P=0.001) were significantly increased in late, stable Ltx (35.4+/-9.6 months after transplantation). Furthermore, increased ADM correlated positively with elevated creatinine (r=0.76, P=0.01) and ANP (r=0.64, P=0.04) after liver transplantation. CONCLUSIONS: Liver-transplant patients exhibit a sustained increase in circulating ADM. Such an increase likely results from renal impairment associated with volume regulation abnormalities, suggesting a potential role for ADM in volume regulation after liver transplantation.     

Tissue-Specific Methylation of Human Insulin Gene and PCR Assay for Monitoring Beta Cell Death

The onset of metabolic dysregulation in type 1 diabetes (T1D) occurs after autoimmune destruction of the majority of pancreatic insulin-producing beta cells. We previously demonstrated that the DNA encoding the insulin gene is uniquely unmethylated in these cells and then developed a methylation-specific PCR (MSP) assay to identify circulating beta cell DNA in streptozotocin-treated mice prior to the rise in blood glucose. The current study extends to autoimmune non-obese diabetic (NOD) mice and humans, showing in NOD mice that beta cell death occurs six weeks before the rise in blood sugar and coincides with the onset of islet infiltration by immune cells, demonstrating the utility of MSP for monitoring T1D. We previously reported unique patterns of methylation of the human insulin gene, and now extend this to other human tissues. The methylation patterns of the human insulin promoter, intron 1, exon 2, and intron 2 were determined in several normal human tissues. Similar to our previous report, the human insulin promoter was unmethylated in beta cells, but methylated in all other tissues tested. In contrast, intron 1, exon 2 and intron 2 did not exhibit any tissue-specific DNA methylation pattern. Subsequently, a human MSP assay was developed based on the methylation pattern of the insulin promoter and human islet DNA was successfully detected in circulation of T1D patients after islet transplantation therapy. Signal levels of normal controls and pre-transplant samples were shown to be similar, but increased dramatically after islet transplantation. In plasma the signal declines with time but in whole blood remains elevated for at least two weeks, indicating that association of beta cell DNA with blood cells prolongs the signal. This assay provides an effective method to monitor beta cell destruction in early T1D and in islet transplantation therapy.     

Insulinoma diagnosed in the postpartum: clinical and immunohistochemical features

Insulinomas are rare pancreatic β-cell tumors with an estimated incidence of 1:250.000 persons/year. We present a novel case of insulinoma manifesting immediately after childbirth. Eight days after delivery, a 21-year-old, previously healthy woman presented paresthesia in hands, upper and lower limbs muscle weakness with difficult walking, which worsened during breastfeeding sessions. Laboratory tests showed blood glucose levels between 37 and 55 mg/dL with inappropriately normal insulin levels (7.78 μUI/mL; normal range: 5-29). An abdominal computed tomography showed a nodular lesion measuring 2 cm at the head of the pancreas. Tumor enucleation resulted in complete resolution of hypoglycemia. Histopathological and immunohistochemical analysis were consistent with an insulinoma. About 27 cases of insulinoma associated with pregnancy have been reported to date, mostly diagnosed before the 16th week. The beginning of symptoms soon after delivery is less common. Understanding the interactions between pancreatic β-cell function and all the physiological metabolic and hormonal adaptations associated with gestation is essential for the adequate management of hypoglycemic disorders in pregnant women.     

Hormonal and metabolic response to physical exercise, fasting and cold exposure in the rat. Effects on ketogenesis in isolated hepatocytes

Four groups of rats were subjected to the following conditions: (1) 48 h fasting, (2) 48 h of 4 degrees C cold exposure, (3) 5 h treadmill running, (4) 48 h fasting with 4 degrees C cold exposure. The groups were compared to fed control rats in order to study hormonal and metabolic responses in blood and tissue samples. Isolated hepatocytes were used to evaluate the rate of ketogenesis. Decreases in liver glycogen and increases in blood free fatty acids (FFA) confirmed that glycogenolysis and lipolysis occur in these situations of metabolic stress. Increases in the glucagon/insulin plasma ratio were also noted. Plasma catecholamine levels were only enhanced after running and after cold exposure. Production of blood ketone bodies was stimulated more by running and by fasting than by cold exposure. The low ketone body production observed after cold exposure seems to be linked to increases liver glycogen levels and decreased FFA availability. Liver cells isolated after cold exposure exhibited higher ketogenesis than these isolated after running. This difference in ketogenic capacity could result both from the longer hormonal stimulation by high glucagon/insulin plasma ratios and from the metabolic state of the liver.     

Effect of subcutaneous pancreatic tissue transplants on streptozotocin-induced diabetes in rats. III. Distribution of neuropeptides in normal and diabetic (host) pancreas.

This study examines whether there is a change in the pattern of distribution of cholecystokinin-octapeptide (CCK-8), calcitonin-gene-related peptide (CGRP), neuropeptide-Y (NPY), substance P (SP) and vasoactive intestinal polypeptide (VIP) in the pancreas of streptozotocin (STZ)-diabetic (host) rats after subcutaneous pancreatic transplantation. Varicose CCK-8-immunopositive nerve fibres were observed in the wall of blood vessels of both normal and diabetic host pancreata. The density of CCK-8-immunoreactive varicose nerve fibres appeared to have increased in host rat pancreas. CGRP was demonstrated in many nerve fibres located in the wall of blood vessels of both normal and host pancreas. CGRP, however, seemed to be better expressed in the nerves of host pancreas when compared to normal. The pancreata of both normal and diabetic (host) rats contained numerous NPY-immunopositive varicose nerve fibres located in the wall of blood vessels. SP was demonstrated in neurons located in the interlobular areas of normal tissue and in fine varicose nerve fibres of the interacinar region of the pancreas of STZ-induced diabetic rats with SPTG. In normal pancreatic tissue, VIP-immunopositive nerve fibres were observed in all areas of the pancreas. VIP-positive nerve fibres were still discernible especially in the interacinar regions of the pancreas of host rats. In conclusion, the pattern of distribution and density of NPY, SP and VIP in the pancreas of STZ-induced diabetic rats with SPTG is similar to that observed in normal pancreas, but the expression of CGRP and CCK-8 seemed to have increased as a result of transplantation and or diabetes.     

The effect of three days of blood glucose normalization by means of an "artificial endocrine pancreas" on the concentrations of growth hormone, glucagon, and cortisol in juvenile diabetics.

Glucagon, growth hormone, and cortisol secretion was studied in seven male insulin-dependent diabetics under conventional subcutaneous insulin therapy and after three days of blood glucose normalization attained by the artificial endocrine pancreas (Biostator-GCIIS). The diurnal hormonal profiles under the two types of therapy were compared. Six healthy male students served as control group. A three-day period of blood glucose normalization in insulin-dependent diabetic can restore glucagon secretion to normal. Growth hormone secretion is decreased but not completely normalised. Cortisol secretion is slightly decreased. It is concluded that prolonged normoglycemia achieved by means of an artificial endocrine pancreas may completely control endocrine abnormalities in insulin-dependent diabetics.     

Metabolic consequences of growth hormone treatment in paediatric practice

No metabolic side-effects of clinical significance have been reported during a 5-year study of growth hormone (GH) therapy in children with GH deficiency, Turner syndrome, idiopathic short stature or chronic renal insufficiency. In particular, insulin levels increase but remain within the normal range, as do glucose and haemoglobin A(1c). A recent study showed that the effects of growth on insulin sensitivity in prepubertal children with idiopathic short stature represent the changes in carbohydrate tolerance observed during normal adolescence. Thus, GH treatment may lead to prolongation of the physiological state of insulin resistance observed in normal puberty. Insulin levels during the fasting state and 2 h after a standard glucose load showed no further rise after the first 3 years of continuous GH therapy. The hyperinsulinaemia observed during GH therapy may, therefore, amplify the anabolic effects of insulin on protein metabolism during puberty.     

Regulatory effects of insulin and experimental diabetes on neutral amino acid transport in the perfused rat exocrine pancreas. Kinetics of unidirectional L-serine influx and efflux at the basolateral plasma membrane

Relatively little is known about the hormonal regulation of amino acid transport in the normal and diabetic exocrine pancreas. In this study unidirectional influx and tracer efflux of L-serine at the basolateral interface of the rat pancreatic epithelium was investigated in the perfused exocrine pancreas using a rapid (less than 30 s) paired-tracer dilution technique. In the non-diabetic pancreas L-serine influx was saturable and stimulated by perfusion with exogenous bovine insulin (100 microU/ml). Transport of L-serine and methylaminoisobutyric acid was markedly elevated in pancreata isolated from streptozotocin diabetic rats and insulin partially reversed the stimulation of L-serine transport induced by experimental diabetes. These results suggest that insulin and diabetes modulate the epithelial transport activity for small neutral amino acids in the intact exocrine pancreas.     

Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome

The polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, is one of the most common hormonal disorders among premenopausal women and is associated with infertility, obesity, and insulin resistance. Accumulating evidence suggests a role of the blood coagulation factor gene F13A1 in obesity (GeneBank ID: NM_000129.3). The aim of this study was to investigate the association of intronic allelic variants of the F13A1 gene with PCOS susceptibility and metabolic parameters in lean and obese PCOS women. In a case-control study, we determined an intronic F13A1 single nucleotide polymorphism (SNP) (dbSNP ID: rs7766109) in 585 PCOS and 171 control women and tested for PCOS susceptibility and associations with anthropometric, metabolic and hormonal parameters. Genotype frequencies of the F13A1 SNP rs7766109 were equivalent in PCOS and control women. In PCOS women, F13A1 gene variants were significantly associated with body mass index (BMI) (p=0.013), systolic blood pressure (p=0.042), insulin response (AUCins) (p=0.015), triglycerides (TG) (p=0.001), and high density lipoprotein cholesterol (HDL) (p=0.012). In the subgroup of obese PCOS women free androgen index (FAI), free testosterone and sex hormone binding globulin (SHBG) as well as glucose measurements showed a significantly different pattern across F13A1 gene variants (p=0.043; p=0.039 and p=0.013, respectively). We report for the first time an association of the F13A1 SNP rs7766109 with BMI, androgens, and insulin resistance in PCOS women. Further studies are needed to confirm our findings and to evaluate whether F13A1 is causally involved in the pathogenesis of PCOS related metabolic and hormonal disturbances.     

Postnatal pancreatic islet β cell function and insulin sensitivity at different stages of lifetime in rats born with intrauterine growth retardation

Epidemiological studies have linked intrauterine growth retardation (IUGR) to the metabolic diseases, consisting of insulin resistance, type 2 diabetes, obesity and coronary artery disease, during adult life. To determine the internal relationship between IUGR and islet β cell function and insulin sensitivity, we established the IUGR model by maternal nutrition restriction during mid- to late-gestation. Glucose tolerance test and insulin tolerance test (ITT) in vivo and glucose stimulated insulin secretion (GSIS) test in vitro were performed at different stages in IUGR and normal groups. Body weight, pancreas weight and pancreas/body weight of IUGR rats were much lower than those in normal group before 3 weeks of age. While the growth of IUGR rats accelerated after 3 weeks, pancreas weight and pancreas/body weight remained lower till 15 weeks of age. In the newborns, the fasting glucose and insulin levels of IUGR rats were both lower than those of controls, whereas glucose levels at 120 and 180 min after glucose load were significantly higher in IUGR group. Between 3 and 15 weeks of age, both the fasting glucose and insulin levels were elevated and the glucose tolerance was impaired with time in IUGR rats. At age 15 weeks, the area under curve of insulin (AUCi) after glucose load in IUGR rats elevated markedly. Meanwhile, the stimulating index of islets in IUGR group during GSIS test at age 15 weeks was significantly lower than that of controls. ITT showed no significant difference in two groups before 7 weeks of age. However, in 15-week-old IUGR rats, there was a markedly blunted glycemic response to insulin load compared with normal group. These findings demonstrate that IUGR rats had both impaired pancreatic development and deteriorated glucose tolerance and insulin sensitivity, which would be the internal causes why they were prone to develop type 2 diabetes.     

Effect of Fenfluramine on Human Growth Hormone Release

In order to investigate the effect of fenfluramine on hormonal and metabolic changes with exercise, five normal volunteers have been studied during and after 20 minutes of steady exercise on a bicycle ergometer after injection of fenfluramine (20 mg intravenously). Fenfluramine abolished the rise of plasma human growth hormone (HGH) which occurred in control investigations. Fenfluramine also affected plasma insulin, blood glucose, and ketone body levels.The acute effect of fenfluramine on the release of growth hormone was examined further by studying its effect in patients with acromegaly. A marked depression of growth hormone occurred both at rest and with exercise. These observations indicate that fenfluramine has a direct effect on pathways controlling growth hormone release. We also suggest that this action may have practical use in the medical treatment of acromegaly.     

Pancreas and Kidney Transplantation Using Embryonic Donor Organs

One novel solution to the shortage of human organs available for transplantation envisions ‘growing’ new organs in situ. This can be accomplished by transplantation of developing organ anlagen/primordia. We and others have shown that renal anlagen (metanephroi) transplanted into animal hosts undergo differentiation and growth, become vascularized by blood vessels of host origin and exhibit excretory function. Metanephroi can be stored for up to 3 days in vitro prior to transplantation with no impairment in growth or function post-implantation. Metanephroi can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. Similarly, pancreatic anlagen can be transplanted across concordant and highly disparate barriers, and undergo growth, differentiation and secrete insulin in a physiological manner following intra-peritoneal placement. Implantation of the embryonic pancreas, is followed by selective differentiation of islet components. Here we review studies exploring the potential therapeutic applicability for organogenesis of the kidney or endocrine pancreas.     

Peptic ulceration,gastric secretion,and renal transplantation.

Fifty-four patients on haemodialysis for chronic renal failure underwent renal transplantation. Basal and maximum acid output and the incidence of peptic ulcer before transplantation were not significantly different from those of controls. But after renal transplantation the incidence of symptoms of peptic ulcer was high (22%) and four out of six patients who developed gastrointestinal bleeding died from this complication. In men peak acid output was significantly increased after renal transplantation and was associated with a 30% incidence of symptoms of peptic ulcer compared with 10% in women, who showed no significant change in mean basal or peak acid output. Peptic ulceration after transplantation was not associated with steroid dosage, hyperparathyroidism, or the height of blood urea concentrations. Given criteria of a history of dyspepsia, abnormal barium meal findings, or gastric hypersecretion, it was not possible to identify patients at risk from peptic ulceration or life-threatening complications after renal transplantation. Thus the routine screening of these patients for peptic ulcer has no practical value, and the incidence of fatal complications is not high enough to justify routine prophylactic anti-ulcer surgery aimed at reducing acid secretion before renal transplantation.     

Insulin substitution: new insulins, new modes of delivery

The demonstrated role of the tight control of hyperglycaemia for the prevention of long-term diabetic complications has reoriented the goals of insulin supply toward the search for restoration of the effects of physiological insulin secretion rather than the simple survival of insulin deficient patients and the reduction in the number of daily insulin injections to be performed. Normal blood glucose control requires the availability of a fast-acting insulin therapy at meal time in order to reduce hyperglycaemic excursions and a basal insulin therapy able to stabilize blood glucose between meals. Reduction of induced hypoglycaemic risk represents the secondary objective beside the main goal of avoiding hyperglycaemia. Fast-acting analogues, by a faster dissociation of their hexameric conformation after their injection or infusion in subcutaneous tissue, reduce post-meal hyperglycaemia, while their shortened duration of action versus regular insulin minimizes late post-absorptive risk of hypoglycaemia. Long-acting analogues, by their precipitation in subcutaneous tissue or their slowly reversible binding to albumin, provide a benefit on blood glucose stability versus NPH or zinc insulins. Continuous insulin therapy using pumps offers both a better blood glucose stability than multiple daily injections and a broader flexibility in life mode. Using the peritoneal route by implantable pumps is a mean to improve blood glucose stability in poorly controlled patients in spite of optimized subcutaneous insulin therapy. The development of glucose sensors provides reinforced information on blood glucose, versus self-monitoring by capillary blood measurements, that contributes to a better adaptation of insulin therapy. First trials of connections between blood glucose data and insulin delivery open a perspective toward glucose-modulated insulin therapy, at least in periods outside meals, leading to first models of semi-automated artificial endocrine pancreas. The alternative of a cellular insulin supply by pancreas or islet transplantation looked promising during recent years, but lack of transplants and adverse events related to immune suppression limit their use to very specific cases where benefit/risk ratio is positive.     

Pregnancy and diabetes: the maternal response

Pregnancy places remarkable stresses on maternal carbohydrate metabolism and pancreatic insulin reserves. The normal mammal responds to pregnancy by increasing pancreatic islet size and insulin secretion. Pregnancy also causes alterations in concentrations of metabolic fuels in maternal circulation. These changes are partly attributed to gestational increases of estrogen, progesterone and human chorionic somatomammotropin, and are thought to provide a proper metabolic and hormonal incubation medium for the fetus. Conversely, the compromised pancreas of the diabetic is unable to meet the additional demands of pregnancy, and carbohydrate metabolism deteriorates. The character of these metabolic changes depends on the time of gestation and the type of diabetes mellitus.     

Effect of subcutaneous pancreatic tissue transplants on streptozotocin-induced diabetes in rats. II. Endocrine and metabolic functions.

The present study examines the effect of subcutaneous pancreatic tissue grafts (SPTG) on endocrine and metabolic functions in streptozotocin (STZ)-induced diabetic rats using radioimmunoassay and biochemical techniques. SPTG survived even after 15 weeks of transplantation and significantly improved the weight of STZ-diabetic rats over a 15-week period. Although blood glucose-, cholesterol-, and glycosylated-haemoglobin (GHb) levels were not significantly lower in STZ-diabetic rats treated with SPTG, the values of these biochemical parameters were lower than those in untreated diabetic rats. Plasma and pancreatic immunoreactive C-peptide (IRCP) levels did not improve after SPTG (IRCP expressed as mean +/- standard deviation were 0.22 +/- 0.07, 0.072 +/- 0.02 and 0.08 +/- 0.03 pg ml-1 in the plasma non-diabetic diabetic and treated rats respectively, while IRCP levels in the pancreas of the non-diabetic, diabetic and treated rats were 433.8 +/- 0.1, 22.9 +/- 0.01 and 10.4 +/- 0.01 pg mg tissue-1 respectively). SPTG, however, improved plasma immunoreactive insulin (IRI) levels in both plasma and pancreas. IRI values in plasma were 54.7 +/- 13.6, 18.0 +/- 5.0 and 22.1 +/- 4.3 microUI ml-1 in non-diabetic, diabetic and treated rats respectively and were 277.3 +/- 37.1, 14.7 +/- 1.8 and 30.3 +/- 15.9 microIU micrograms tissue-1 in the pancreas of non-diabetic, diabetic and treated rats respectively. There was improvement in immunoreactive glucagon (IRG) levels after SPTG. IRG values in the plasma of non-diabetic, diabetic and treated rats were 147.0 +/- 10.7, 408.0 +/- 76.5 and 247.7 +/- 3 pg ml-1 respectively whereas, IRG measured in the pancreas was 1642.25 +/- 424.23, 1899.0 +/- 290.4 and 1714.1 +/- 301.98 pg micrograms tissue-1 in non-diabetic, diabetic and treated rats, respectively. The pancreas:plasma ratio of pancreatic hormones was deranged in untreated diabetes but improved after SPTG. In conclusion, SPTG significantly improved the weight gain, pancreatic insulin content, plasma IRG and pancreas: plasma ratio of IRCP, IRI and IRG. It also reduced blood glucose-, cholesterol-, and glycosylated-hemoglobin levels in STZ-diabetic rats.