Different genetic backgrounds for malnutrition-related diabetes and Type 1 (insulin-dependent) diabetes mellitus in South Indians

Summary HLA-DRB, -DQA and -DQB genes were studied in ten South Indian malnutrition-related diabetic patients, ten Type 1 (insulin-dependent) diabetic patients and 45 control subjects, by TaqI restriction fragment length polymorphism analysis. The DR7,DQw9 haplotype was found to be frequent in patients with malnutrition-related diabetes (p<0.01). The DRw17,DQw2 haplotype was overrepresented in the patients with Type 1 diabetes compared to control subjects (p<0.05). In vitro amplification of the polymorphic second exon of DQB genes by the polymerase chain reaction technique was performed on DNA from 10 malnutrition-related diabetic patients, 10 Type 1 diabetic patients and 13 control subjects, as they belong to a new population. Hybridization with sequence-specific oligonucleotide probes for DQB1 alleles showed homozygosity of aspartic acid at position 57 in 7 of 10 malnutrition-related diabetic patients compared to 2 of 10 Type 1 diabetic (p<0.05) and 15 of 45 control subjects (p<0.05). Homozygosity of non-aspartic acid at position 57 was present in 7 of 10 Type 1 diabetic compared to 0 of 10 malnutrition-related diabetic patients (p<0.005) and 3 of 45 control subjects (p<0.05). This study has confirmed the association of DQB1 57 non-asp in South Indians with Type 1 diabetes. In addition, our data clearly show that the genetic background of malnutrition-related diabetes mellitus is different from that of Type 1 diabetes.     

Diagnostic criteria for acute‐onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute‐onset Type 1 Diabetes Mellitus

Type 1 diabetes is a disease characterized by destruction of pancreatic β‐cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute‐onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute‐onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti‐islet autoantibodies are diagnosed with ‘acute‐onset type 1 diabetes mellitus (autoimmune)’. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C‐peptide immunoreactivity <0.6 ng/mL) without verifiable anti‐islet autoantibodies are diagnosed simply with ‘acute‐onset type 1 diabetes mellitus’. Patients should be reevaluated after certain periods in case their statuses of anti‐islet autoantibodies and/or endogenous insulin secretory capacity are unknown.     

Abnormalities in the ultradian oscillations of insulin secretion and glucose levels in Type 2 (non-insulin-dependent) diabetic patients

Summary To investigate the temporal organization of insulin secretion and glucose concentration during fasting in Type 2 (non-insulin-dependent) diabetes mellitus, we studied seven patients with Type 2 diabetes, eight obese non-diabetic control subjects and eight normal weight non-diabetic subjects. Blood sampling for glucose, insulin and C-peptide was performed at 15-min intervals during a 24-h period of fasting for the diabetic and the obese control subjects and during an 8-h fasting period for the normal subjects. Insulin secretion rates were calculated from the peripheral C-peptide concentration profiles. Ultradian oscillations of glucose levels and insulin secretion rates were evident during fasting in all subjects. An additional study with blood sampling at 2-min intervals for 8 h further indicated that this ultradian periodicity is expressed independently of rapid 10–15 min insulin oscillations. There were no differences between diabetic and nondiabetic subjects in the frequency of the ultradian oscillations of insulin secretion (which averaged 12–15 oscillations per 24 h) and in the rate of concomitancy of oscillations of insulin secretion with oscillations in glucose levels, which averaged 63–65%. The relative amplitudes of both the insulin and glucose oscillations were also similar in diabetic and nondiabetic subjects. The major abnormality in patients with Type 2 diabetes was evidenced by spectral analysis, and confirmed by calculations of the distributions of inter-pulse intervals. It consisted of a slowing of the glucose oscillations, without a similar slowing of the oscillations in insulin secretion. This slowing of the glucose oscillations in fasting Type 2 diabetic patients is consistent with our previous observations of sluggish and irregular glucose oscillations in diabetic subjects receiving mixed meals. This partial dissociation between the oscillatory patterns of insulin secretion and glucose levels could represent a sensitive quantitative marker of the breakdown of the insulin-glucose feedback loop in diabetes.     

Plasma Concentrations of Islet Amyloid Polypeptide After Glucagon Administration in Type 2 Diabetic Patients and Non-diabetic Subjects

Islet amyloid polypeptide (IAPP) is the main constituent of pancreatic islet amyloid, observed in the pancreases from patients with Type 2 diabetes mellitus. IAPP is synthesized by the pancreatic β-cells. In order to study the secretion characteristics of IAPP in Type 2 diabetes mellitus, plasma IAPP was measured during a provocation test with glucagon in 33 Type 2 diabetic patients and 18 non-diabetic subjects. The median fasting IAPP level was 5.7 (range 1.1–13.1) pmol l^?1 in the 27 patients treated with oral hypoglycaemic agents and 2.7 (1.9–5.9) in the 6 patients on insulin. In the non-diabetic group fasting IAPP was 5.7 (2.2–10.1). Six minutes after glucagon administration median IAPP rose to 9.4 (1.7–31.0) and 6.1 (5.1–10.2) in the respective diabetic groups, and to 16.8 (4.0–41.0) in the non-diabetic subjects (p 0.05). The correlation coefficient between change in IAPP and change in C-peptide was 0.68 in the diabetic group. We conclude that intravenous administration of glucagon stimulates IAPP release from the β-cell. This provocation test is easy to perform and can be used on a large scale in the study of IAPP secretion in Type 2 diabetes mellitus.     

Cellular and humoural autoimmunity markers in Type 2 (non-insulin-dependent) diabetic patients with secondary drug failure

Summary In some cases patients with Type 2 (non-insulin-dependent) diabetes mellitus fail to respond to treatment with oral hypoglycaemic agents. These patients may respond in the same way as Type 1 (insulin-dependent) diabetic patients. Cellular immune aggression (defined as the capacity of peripheral mononuclear cells to inhibit stimulated insulin secretion by dispersed rat islet cells), insulin autoantibodies, C-peptide response and HLA antigens were determined in 31 Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents and in 22 control subjects. Nine (29.03%) of the 31 Type 2 diabetic patients showed positive cellular immune aggression (2 SD below control group) and 22 (70.97%) presented no cellular immune aggression. There was a relationship between positive cellular immune aggression and each of the following parameters: age, body mass index and microangiopathy. No correlation was found between positive cellular immune aggression and glycaemia, HbA₁, blood lipids or atherosclerosis. Patients with positive cellular immune aggression showed a significantly lower glucagon-stimulated C-peptide response vs those with no cellular immune aggression. Within a sub-group of patients who had never been treated with insulin, insulin autoantibodies were present in four of six patients with positive cellular immune aggression. DR2 antigen was found with decreased frequency in patients whereas no DR3/DR4 heterozygotes were observed. Our data support the hypothesis that a group of Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents presented autoimmunity towards pancreatic Beta cells.     

Type 2 diabetes and beta cell apoptosis

Type 2 diabetes mellitus features an asymptomatic insulin resistance phase preceding the onset of diabetes. Hyperglycemia occurs when a relative insulin deficiency appears, meaning that beta cell secretory dysfunction is a key element in type 2 diabetes pathophysiology. So far, insulin secretion deficiency is explained by pancreatic beta cell "exhaustion" phenomena. Recent data suggest that apoptotic mechanisms could explain insulin deficiency through a reduction in the absolute pancreatic beta cell number. Psammomys obesus (sand rat) is an animal model for type 2 diabetes mellitus, initially characterized by hyperinsulinism followed by insulin deficiency linked with a reduction in the number of pancreatic beta cells. Transition to diabetes can be observed following changes in usual lifestyle of the sand rat. In the desert, caloric intake is low and physical expenditure is heavy. In the laboratory, animals turn diabetic as early as 4 days following a high calorie diet. At a later stage, diabetes is irreversible and animals die from diabetic ketoacidosis. beta cell apoptosis rate is low in non diabetic animals and increases 14-fold by 20 days after diabetes onset. At this stage, cells undergoing apoptosis can be observed, coexisting with necrotic cells without any insulitis. Similar results were obtained in vitro in isolated pancreatic islets that were exposed to increasing glucose concentrations, suggesting that chronic hyperglycemia plays a role in the onset or the deterioration of the process. However, precise mechanisms of apoptosis in this case remain poorly understood. Aminoguanidin does not prevent beta cell apoptosis in vitro, suggesting that advanced glycation products or NO production are not involved in this beta cell destruction process. Similar mechanisms secondary to hyperglycemia could play a role in the diabetes process in man and explain the marked insulin secretory deficiency that is sometimes observed in these patients. In addition to its preventing role on diabetes complication, the obtention of normoglycemia could help maintaining beta cell function.     

Pathophysiology of ketoacidosis in Type 2 diabetes mellitus.

AIMS: Despite an increasing number of reports of ketoacidosis in populations with Type 2 diabetes mellitus, the pathophysiology of the ketoacidosis in these patients is unclear. We therefore tested the roles of three possible mechanisms: elevated stress hormones, increased free fatty acids (FFA), and suppressed insulin secretion. METHODS: Forty-six patients who presented to the Emergency Department with decompensated diabetes (serum glucose > 22.2 mmol/l and/or ketoacid concentrations > or = 5 mmol/l), had blood sampled prior to insulin therapy. Three groups of subjects were studied: ketosis-prone Type 2 diabetes (KPDM2, n = 13) with ketoacidosis, non-ketosis-prone subjects with Type 2 diabetes (DM2, n = 15), and ketotic Type 1 diabetes (n = 18). RESULTS: All three groups had similar mean plasma glucose concentrations. The degree of ketoacidosis (plasma ketoacids, bicarbonate and anion gap) in Type 1 and 2 subjects was similar. Mean levels of counterregulatory hormones (glucagon, growth hormone, cortisol, epinephrine, norepinephrine), and FFA were not significantly different in DM2 and KPDM2 patients. In contrast, plasma C-peptide concentrations were approximately three-fold lower in KPDM2 vs. non-ketotic DM2 subjects (P = 0.0001). Type 1 ketotic subjects had significantly higher growth hormone (P = 0.024) and FFA (P < 0.002) and lower glucagon levels (P < 0.02) than DM2. CONCLUSIONS: At the time of hospital presentation, the predominant mechanism for ketosis in KPDM2 is likely to be greater insulinopenia.     

The Size of the Pancreas in Diabetes Mellitus

To determine whether there was an association between the size of the pancreas and the type of diabetes, ultrasonography of the pancreas was performed on 57 diabetic patients: 14 with Type 1 (insulin-dependent) diabetes, 10 insulin-treated and 33 tablet-treated patients with Type 2 (non-insulin-dependent) diabetes, and 19 non-diabetic subjects. The pancreas of patients with Type 1 diabetes was markedly smaller (p < 0.0001) than the pancreas in non-diabetic subjects. The pancreas of patients with Type 2 diabetes was more moderate in size: larger (p < 0.001) than that of Type 1 diabetic patients but smaller (p < 0.5) than the pancreas of the control group. Pancreatic size of patients with Type 2 diabetes was also related to basal insulin secretion with insulin-deficient patients (low or undetectable C-peptide) having smaller (p < 0.05) pancreases than those with normal insulin secretion. There was no difference in the size of the pancreas in the different treatment groups of Type 2 diabetic patients. Pancreatic size did not correlate with age, body mass index or the duration of diabetes. We conclude that the pancreas is a smaller organ in patients with diabetes mellitus and that the decrement in size is maximal in insulin-dependent/insulin-deficient subjects. Ultrasonography, therefore, can potentially serve to discriminate between the different types of diabetes.     

Islet transplantation: a realistic alternative for the treatment of insulin deficient diabetes mellitus

Diabetes mellitus is a devastating disease and the WHO [World Health Report, World Health Organization, 2002] (World Health Organization) expects that the number of diabetic patients will increase to 300 million by the year 2025. Type 1 diabetes results from an autoimmune-mediated destruction of the insulin-secreting beta-cells in the islets of Langerhans of the pancreas, whereas Type 2 diabetes is a disease of the older population which is due to systemic insulin resistance and reduced insulin secretion by the pancreatic beta-cells. Surgical resection of the pancreas may also cause insulin-dependent diabetes depending on the size of the remaining pancreas. The long-term complications of diabetes are a direct result of the constantly elevated levels of blood glucose in the absence of an effective insulin treatment. Recent prospective studies such as the diabetes control and complication trial (DCCT) [N. Engl. J. Med. 329 (1993) 977] and the UK prospective diabetes study [Lancet 352 (1998) 837] have convincingly demonstrated that improved blood glucose control in all type diabetes reduces the risk of the development of the secondary complications of diabetes. Despite intensive insulin therapy, most individuals with insulin deficient diabetes are unable to maintain a blood glucose level in the normal range at all times. Therefore, the only way to ensure the long-term health of patients with diabetes is find a way of maintaining constant normoglycemia. It seems logical that the replacement of the islet tissue itself, either by transplanting a vascularized pancreatic allograft or by transplanting purified pancreatic islet cells, offers a better approach than simply replacing insulin that has been lost. In this article, we outline the major achievements made recently in the development of therapeutic islet transplantation applications and offer an explanation as to why islet transplantation seems to be an ideal solution for absolute insulin deficient diabetes.     

Different aetiologies of Type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects

Summary Insulin responses to intravenous glucose infusion and glucose utilization during hyperinsulinaemic euglycaemic clamp were determined in a large homogeneous group of 65-year-old male subjects. Twenty-eight had untreated Type 2 (non-insulin-dependent) diabetes mellitus and the remaining 44 control subjects had a normal glucose tolerance. Diabetic patients with abdominal obesity displayed peripheral insulin resistance in combination with defective insulin secretion, whereas non-obese diabetic patients showed only a secretory defect. Thus, Type 2 diabetes in obese and non-obese elderly male subjects may take two forms where the cause of hyperglycaemia differs.     

Type 2 diabetes presenting as diabetic ketoacidosis in adolescence.

We report two black adolescent subjects who presented with diabetic ketoacidosis, but who lacked autoimmune markers and demonstrated clinical and biochemical characteristics more typical of Type 2 diabetes, including obesity, acanthosis nigricans, positive family history for Type 2 diabetes, and Type 2 diabetic dyslipidaemia. Subsequent to acute presentation, insulin was discontinued in both subjects and excellent glycaemic control was achieved with metformin therapy alone. Four months following acute presentation, both had adequate C-peptide responses to intravenous glucagon. Type 2 diabetes can present as diabetic ketoacidosis in obese adolescent subjects.     

High frequency of class 3 allele in the human insulin gene in Japanese Type 2 (non-insulin-dependent) diabetic patients with a family history of diabetes

Summary The restriction fragment length polymorphism in the 5 flanking region of the human insulin gene was studied in 155 nonobese Japanese subjects. The subjects consisted of 36 Type 2 (non-insulin-dependent) diabetic patients with a family history of diabetes mellitus, 42 Type 2 diabetic patients without a family history of diabetes, 42 Type 1 (insulin-dependent) diabetic patients, and 35 healthy volunteers who served as control subjects. It was demonstrated that, in Japanese healthy subjects and diabetic patients, the incidence of the insertion into 5 flanking region of the insulin gene was found to be significantly lower (p<0.05) than those in Caucasians and other races already investigated. Even though the class 3 gene allelic frequency in Type 2 diabetic patients without a family history of diabetes (0.060) was not higher than that in healthy subjects (0.014), in nonobese Type 2 diabetic patients with a family history of diabetes the allelic frequency of the inserted class 3 gene (0.111) was found to be significantly higher (p<0.02) than that in control subjects. These data suggest that the insulin gene polymorphism relates to the aetiology of diabetes mellitus.     

Disproportionate elevation of immunoreactive proinsulin in Type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance

Summary In this study, we found that the ratio of proinsulin to total immunoreactive insulin was much higher in 22 patients with Type 2 (non-insulin-dependent) diabetes mellitus than in 28 non-diabetic control subjects of similar age and adiposity (32±3 vs 15±1%, p<0.001). In addition, the arginine-induced acute proinsulin response to total immunoreactive insulin response ratio was greater in diabetic patients (n=10) than in control subjects (n=9) (8±2 vs 2±0.5%, p=0.009), suggesting that increased islet secretion per se accounted for the increased ratio of proinsulin to immunoreactive insulin. One explanation for these findings is that increased demand for insulin in the presence of islet dysfunction leads to a greater proportion of proinsulin secreted from the B cell. We tested this hypothesis by comparing proinsulin secretion before and during dexamethasone-induced insulin resistance in diabetic patients and control subjects. Dexamethasone treatment (6 mg/day for 3 days) raised the proinsulin to immunoreactive insulin ratio in control subjects from 13±2 to 21±2% (p<0.0001) and in diabetic patients from 29±5 to 52±7% (p<0.001). Dexamethasone also raised the ratio of the acute proinsulin response to the acute immunoreactive insulin response in control subjects from 2±0.5 to 5±2% (p=0.01) and in diabetic patients from 8±2 to 14±4% (p=NS), suggesting that the dexamethasone-induced increment in the basal ratio of proinsulin to immunoreactive insulin was also due to increased secretion. We conclude that: (1) The basal proinsulin to immunoreactive insulin ratio is increased in obese Type 2 diabetic patients. (2) An increase in tissue demand for insulin leads to a rise in the proinsulin to immunoreactive insulin ratio, which is exaggerated in Type 2 diabetic patients. (3) The increased proinsulin to immunoreactive insulin ratio in these diabetic patients in the basal state and in diabetic patients and control subjects during experimental insulin resistance is probably due to increased B-cell secretion of proinsulin.     

Effect of growth hormone releasing hormone on growth hormone secretion in Type 2 (non-insulin-dependent) diabetes mellitus

Summary Growth hormone levels following an intravenous bolus injection of 1 g/kg body weight growth hormone releasing hormone were measured in 21 non-obese and 26 obese patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 13 control subjects. Growth hormone responses in non-obese Type 2 diabetic patients were not statistically different from control subjects. However, obese Type 2 diabetic patients had significantly decreased growth hormone responses to growth hormone releasing hormone when compared with non-obese Type 2 diabetic patients (p<0.02). In 9 Type 2 diabetic patients growth hormone releasing hormone tests were performed both during hyperglycaemia and after metabolic improvement by insulin treatment. Growth hormone responses before and after insulin treatment were not statistically different. Our data demonstrate that (1) growth hormone responses to growth hormone releasing hormone in non-obese Type 2 diabetic patients do not differ significantly from control subjects; (2) obesity blunts growth hormone responses to growth hormone releasing hormone in Type 2 diabetes mellitus; and (3) growth hormone responses following growth hormone releasing hormone administration in Type 2 diabetes mellitus are not influenced by the state of metabolic control.     

Erythromycin improves glycaemic control in patients with Type II diabetes mellitus

Aims/hypothesis. Erythromycin mimics the effect of the gastrointestinal hormone motilin by binding to its receptor and acting as a motilin agonist. We recently found that motilin stimulates insulin secretion at lower doses than doses required to stimulate gastric contractile activity. We studied the effects of erythromycin on insulin secretion and glycaemic control in patients with diabetes mellitus.¶Methods. Inpatients (n = 34) with Type II (non-insulin-dependent) diabetes mellitus were randomly assigned to receive either erythromycin (400 mg orally three times a day, n = 19) or a placebo (n = 15) for 1 week (first study). Another 34 outpatients with Type II diabetes were also treated with erythromycin (200 mg orally three times a day, n = 17) or a placebo (n = 17) for 4 weeks (second study). Finally, nine inpatients with Type II diabetes and eight normal control subjects received intravenous erythromycin (10 mg · kg^–1· h^–1) or saline infusion and insulin secretion was examined (third study).¶Results. Erythromycin lowered fasting blood glucose and fructosamine concentrations (p < 0.01) and increased basal as well as glucose-stimulated insulin secretion (p < 0.05–0.01) (first study). Low doses of erythromycin treatment for 4 weeks also significantly improved glycaemic control in Type II diabetic patients (second study). Erythromycin infusion significantly increased plasma insulin and decreased glucose concentrations in Type II diabetic and control subjects and greatly potentiated glucose-induced insulin secretion in the latter (third study).¶Conclusion/interpretation. These results indicate that erythromycin given orally has an antidiabetogenic effect and therefore erythromycin derivatives that lack the antibacterial activity could have a therapeutic value in Type II diabetic patients. [Diabetologia (2000) 43: 411–415]     

Sudden onset of diabetes with ketoacidosis in a patient treated with FK506/tacrolimus

We report a 43-year-old man who presented diabetic ketoacidosis 1 year after receiving kidney transplantation. He was a recipient of renal transplantation treated with metyl-prednisolone and tacrolimus regimen. The serum level of tacrolimus was 12.4 ng/ml, and he showed hyperphagia before a month of admission. A week before admission, he was aware of polydipsia, polyuria, and general fatigue. He visited our hospital and was found to have severe hyperglycemia (925 mg/dl), significant ketosis and mild metabolic acidosis (pH 7.341), although he had not been diagnosed as diabetes mellitus. He administrated in our hospital, and was treated with insulin for 5 weeks. He was not obese (BMI = 18.2 kg/m(2)) and had no family history of type 2 diabetes. He was finally treated with diet therapy alone. The 24 h urine C-peptide secretion on the third hospital day was low (8.4 microg per day). However, no autoantibodies against pancreatic islets were positive, and his insulin secretion was recovered at discharge suggesting that he was not type 1 diabetes. Although, tacrolimus has been reported to cause or worsen diabetes mellitus, the present case suggests that it could cause severe decrease in insulin secretion which leading to diabetic ketoacidosis in lean subject without previous history of diabetes mellitus.     

Gene therapy for diabetes mellitus in rats by hepatic expression of insulin.

Type 1 diabetes mellitus is caused by severe insulin deficiency secondary to the autoimmune destruction of pancreatic beta cells. Patients need to be controlled by periodic insulin injections to prevent the development of ketoacidosis, which can be fatal. Sustained, low-level expression of the rat insulin 1 gene from the liver of severely diabetic rats was achieved by in vivo administration of a recombinant retroviral vector. Ketoacidosis was prevented and the treated animals exhibited normoglycemia during a 24-hr fast, with no evidence of hypoglycemia. Histopathological examination of the liver in the treated animals showed no apparent abnormalities. Thus, the liver is an excellent target organ for ectopic expression of the insulin gene as a potential treatment modality for type 1 diabetes mellitus by gene therapy.     

Insulin-like growth factor binding protein 1 response to acute insulin induced hypoglycaemia in Type 1 diabetes

OBJECTIVES Insulin Is believed to be the prime regulator of Insulin-like growth factor binding protein 1 (IGFBP-1) secretion, and In normal subjects acute insulin Induced hypoglycaemla exerts a rapid effect on concentrations of IGFBP-1, and may also Influence Insulin-like growth factor I (IGF-I) concentrations. The rise In IGFBP-1 concentrations in normal subjects following hypoglycaemia has been suggested to be due to suppression of endogenous insulin secretion. We have examined this further by studying diabetics with no endogenous Insulin secretion. DESIGN We have compared the IGFBP-1 response to acute insulin Induced hypoglycaemia in normal subjects and patients with Type 1 (insulin dependent) diabetes mellitus. METHODS Insulin tolerance test8 were performed using a bolus of Insulin (0·15 U/kg), in six control subjects and six patients with Type 1 diabetes. MEASUREMENTS Serum levels of IGFBP-1, insulin, glucose, and IGF-I were measured at regular Intervals during the insulin tolerance test. RESULTS Blood glucose fell to a nadir which coincided with the onset of the acute autonomic reaction ‘R’ In both groups. The basal concentration of IGF-I was significantly lower In the diabetic group at 0·4 ± 0·1 kU/l, compared to 0·9 ± 0·1 kU/l In the control group, but there was no significant change In IGF-I concentrations In response to hypoglycaemia In either group. Hypoglycaemia provoked a fall In IGFBP-1 In patients with Type 1 diabetes, from 38 ± 9 μg/l basally to 17 ± 3 μg/l at R + 120 minutes, with a return to basal values of 45 ± 11 μg/l at R + 180 minutes. In the control subjects there was no fall In IGFBP-1, but a significant Increase to 71 ± 14 μg/l at R + 180 minutes. CONCLUSION This difference In the IGFBP-1 response In the presence of a similar glucose response suggests that In Type 1 diabetes there may be different sensitivities to the actions of exogenous Insulin on IGFBP-1 regulation.     

Modestly increased beta cell apoptosis but no increased beta cell replication in recent-onset type 1 diabetic patients who died of diabetic ketoacidosis

Aims/hypothesis Type 1 diabetes is characterised by a deficit in beta cell mass thought to be due to immune-mediated increased beta cell apoptosis. Beta cell turnover has not been examined in the context of new-onset type 1 diabetes with diabetic ketoacidosis. Methods Samples of pancreas were obtained at autopsy from nine patients, aged 12 to 38 years (mean 24.3±3.4 years), who had had type 1 diabetes for less than 3 years before death due to diabetic ketoacidosis. Samples of pancreas obtained at autopsy from nine non-diabetic cases aged 11.5 to 38 years (mean 24.2±3.4 years) were used as control. Fractional beta cell area (insulin staining), beta cell replication (insulin and Ki67 staining) and beta cell apoptosis (insulin and TUNEL staining) were measured. Results In pancreas obtained at autopsy from recent-onset type 1 diabetes patients who had died of diabetic ketoacidosis, the beta cell deficit varied from 70 to 99% (mean 90%). The pattern of beta cell loss was lobular, with almost all beta cells absent in most pancreatic lobules; islets in lobules not devoid of beta cells had reduced or a near-normal complement of beta cells. Beta cell apoptosis was increased in recent-onset type 1 diabetes, but to a surprisingly modest degree given the marked hyperglycaemia (30 mmol/l), acidosis and presumably high NEFA. Beta cell replication, scattered pancreatic beta cells and beta cells in exocrine ducts were not increased in recent-onset type 1 diabetes. Conclusions/interpretation These findings do not support the notion of active beta cell regeneration by replication in new-onset type 1 diabetes under conditions of diabetic ketoacidosis. The gluco-lipotoxicity reported in isolated human islets may be less evident in vivo.