Duodenal-jejunal bypass normalizes pancreatic islet proliferation rate and function but not hepatic steatosis in hypothalamic obese rats

Modifications in life-style and/or pharmacotherapies contribute to weight loss and ameliorate the metabolic profile of diet-induced obese humans and rodents. Since these strategies fail to treat hypothalamic obesity, we have assessed the possible mechanisms by which duodenal-jejunal bypass (DJB) surgery regulates hepatic lipid metabolism and the morphophysiology of pancreatic islets, in hypothalamic obese (HyO) rats. During the first 5 days of life, male Wistar rats received subcutaneous injections of monosodium glutamate (4 g/kg body weight, HyO group), or saline (CTL). At 90 days of age, HyO rats were randomly subjected to DJB (HyO DJB group) or sham surgery (HyO Sham group). HyO Sham rats were morbidly obese, insulin resistant, hypertriglyceridemic and displayed higher serum concentrations of non-esterified fatty acids (NEFA) and hepatic triglyceride (TG). These effects were associated with higher expressions of the lipogenic genes and fatty acid synthase (FASN) protein content in the liver. Furthermore, hepatic genes involved in β-oxidation and TG export were down-regulated in HyO rats. In addition, these rats exhibited hyperinsulinemia, β-cell hypersecretion, a higher percentage of islets and β-cell area/pancreas section, and enhanced nuclear content of Ki67 protein in islet-cells. At 2 months after DJB surgery, serum concentrations of TG and NEFA, but not hepatic TG accumulation and gene and protein expressions, were normalized in HyO rats. Insulin release and Ki67 positive cells were also normalized in HyO DJB islets. In conclusion, DJB decreased islet-cell proliferation, normalized insulinemia, and ameliorated insulin sensitivity and plasma lipid profile, independently of changes in hepatic metabolism.

Effects of aging on pancreatic islet cell function: an experimental immunohistochemical and ultrastructural study

A strong relationship between aging and diabetes mellitus has been clinically suggested, however, none of the previous published data had clearly focused on the age-related cytomorphological changes in the pancreas which are the goal of this study. Three groups of male apparently healthy rabbits have been used, ten animals each; classified as group-1 [3-5months old]; group-2 [9-12 months old] and group-3 [24-36 months old]. After sacrification, sections from the pancreas were stained by Haematoxylin and Eosin [H and E], Gomori trichromic stain and ultrastructurally to detect aging histologic changes as well as immunohistochemically to identify insulin and glucagon secreting cells using their appropriate monoclonal antibodies. A progressive histological distortion with fibrosis and fatty changes were directly proportional to age, being mild in group-2 and severe in group-3. Morphometric studies by computerized image analysis showed that the mean number of islets was significantly higher in group2 [8.98+/-1.51], lowest in group-1 [5.08+/-1.48] and intermediate in group-3 [6.37+/-1.37]. The mean diameter and square area of islets were significantly higher in group-2 compared to other groups [P< 0.05]. The mean number of beta cells per islet and their secretary granules were significantly [P <0.05] higher in group-2, intermediate in group-1 and lowest in group-3.In contrast, the mean number of alpha cells per islet and their secretory granules were insignificantly [P< 0.05] higher in group -2, intermediate in group-3 and lowest in group-1.Also, the beta/alpha ratio [beta cells/alpha cells] was greatest in group-2 [3.059:1], intermediate in group-1 [3.37:1], and lowest in group-3 [2.479:1]. The increased number of beta cells may be due to a compensatory process to correct the hormonal feedback mechanism of insulin .The results of this work suggest that beta cells are generally more vulnerable to aging, an observation which might be correlated clinically with higher incidence of diabetes in older ages

Genesis de la mellitus tipo 1 / Genesis of the mellitus type I

La incidencia de la Diabetes Tipo 1 ha aumentado durante los últimos decenios en todo el mundo, representando en nuestro medio la séptima causa de muerte y afectando aproximadamente a un millón de venezolanos. De acuerdo a la OMS se clasifica en: Autoinmune (tipo A y tipo B) e idiopática. Esta enfermedad se considera como el resultado de una serie de factores genéticos (asociados a la región HLA-D del MHC clase II; principalmente es el locus HLA-DQ) y ambientales (relacionados con el estilo de vida del paciente e infecciones virales principalemente en virus coxsackie) que medían la activación del sistema inmunológico del individuo provocando de esta manera la destrucción de las células beta pancreáticas por diferentes mecanismos: pérdida de la Autotolerancia, Directo "Reconocimiento de Unión" e Indirecto "Unión-Activación" y como consecuencia la aparición de las manifestaciones clínicas de la enfermedad. La DM tipo 1 cursa con un período asintomático que se caracteriza por una infiltración de los islotes por monocitos/macrófagos y células T citotóxicas activadas. Este estado en el que se encuentran el paciente mientras se está produciendo (de forma indetectable), la agregación inmunitaria se denomina PRE-DIABETES, posteriormente las reservas de insulina van disminuyendo constantemente hasta hacerse insuficientes y es cuando se manifiesta clínicamente la DM.

Early morphological and functional changes in pancreas following necrosectomy for acute severe necrotizing pancreatitis.

INTRODUCTION: Morphological and functional changes in the pancreas after surgical pancreatic necrosectomy have not been studied extensively. AIMS: To study morphological changes in the pancreas, and exocrine and endocrine pancreatic function following pancreatic necrosectomy. METHODS: Eighteen adult patients surviving at least one month after pancreatic necrosectomy for acute necrotizing pancreatitis were followed up. Contrast-enhanced computed tomography was done every six months. Stool fat was estimated at 3-month intervals, and need for and response to enzyme supplements were recorded. Blood sugar was measured every fortnight; in patients with hyperglycemia, need for oral hypoglycemic agents or insulin was recorded. Additional pancreatic imaging was done in some cases. RESULTS: Six weeks after surgery, nine of 18 patients had exocrine insufficiency. Thirteen patients developed endocrine insufficiency, including 5 who also had exocrine insufficiency. At the end of the study, 13 patients had endocrine insufficiency and 2 had exocrine insufficiency. Pancreatic size was subnormal in all patients at the end of six months. Pancreatography in three cases did not reveal any ductal abnormality. CONCLUSIONS: Necrotizing pancreatitis affects pancreatic exocrine or endocrine function in more than half the patients.

The role of diminished beta cell reserve and insulin resistance in secondary sulfonylurea failure of type 2 diabetes mellitus.

INTRODUCTION: The correction of hyperglycemia by insulin treatment has been shown to ameliorate beta cell function and insulin sensitivity in SU failure patients, and there also appears to have disparity between tests of beta cell function among these patients. The objectives of this study were to determine beta cell secretory reserve and insulin resistance of secondary SU failure type 2 diabetic patients who had fairly good glycemic control compared with those who were SU responsive and the disparity of beta cell responses to glucose and non-glucose stimuli were examined in these two groups. SUBJECTS AND METHOD: Eight secondary SU failure, insulin-treated and 11 SU responsive type 2 diabetic patients who were matched for age, degree of obesity, duration of diabetes as well as HbAlc were studied. Intravenous glucagon and oral glucose tolerance tests (OGTT) as well as short intravenous insulin tolerance test using arterialized venous blood were randomly performed on separate occasions to assess beta cell secretory reserve and insulin sensitivity, respectively. RESULTS: Basal (0.37+/-0.05 (SEM) vs 0.80+/-0.14 nmol/l; p=0.02) and stimulated c-peptide levels (0.66+0.08 vs 1.16+/-0.14 nmol/l; p=0.007) after glucagon as well as basal (0.46+/-0.06 vs 0.73+/-0.10 nmol/l; p=0.046) and maximal c-peptide responses (1.41+/-0.14 vs 1.97+/-0.14 nmol/l; p=0.021) to glucose stimulation were significantly lower in SU failure than SU responsive patients. However, the incremental changes of c-peptide over basal after glucagon (0.29+/-0.06 vs 0.37+/-0.09 nmol/l) and glucose (AUC: 36.9+/-7.6 vs 47.9+/-4.5 nmol/l/h) were not different between both groups. There were strong positive relationships between basal and stimulated c-peptide responses to glucagon (r=0.818; p=0.002) and glucose (r=0.85; p=0.001) in SU responsive patients but these relationships were not as strong in SU failure patients (r=0.682; p=0.062 and r=0.41; p=NS, respectively). Insulin sensitivity did not differ between the two groups. CONCLUSION: This study demonstrated that decreased basal, but not stimulated, insulin secretion was possibly a major factor associated with secondary SU failure in type 2 diabetic patients. With comparable glycemic control, there was no disparate beta cell responses to glucose and glucagon in patients with or without secondary SU failure.

Is pancreas development abnormal in the non-obese diabetic mouse, a spontaneous model of type I diabetes?

Despite extensive genetic and immunological research, the complex etiology and pathogenesis of type I diabetes remains unresolved. During the last few years, our attention has been focused on factors such as abnormalities of islet function and/or microenvironment, that could interact with immune partners in the spontaneous model of the disease, the non-obese diabetic (NOD) mouse. Intriguingly, the first anomalies that we noted in NOD mice, compared to control strains, are already present at birth and consist of 1) higher numbers of paradoxically hyperactive ß cells, assessed by in situ preproinsulin II expression; 2) high percentages of immature islets, representing islet neogenesis related to neonatal BETA-cell hyperactivity and suggestive of in utero BETA-cell stimulation; 3) elevated levels of some types of antigen-presenting cells and FasL+ cells, and 4) abnormalities of extracellular matrix (ECM) protein expression. However, the colocalization in all control mouse strains studied of fibroblast-like cells (anti-TR-7 labeling), some ECM proteins (particularly, fibronectin and collagen I), antigen-presenting cells and a few FasL+ cells at the periphery of islets undergoing neogenesis suggests that remodeling phenomena that normally take place during postnatal pancreas development could be disturbed in NOD mice. These data show that from birth onwards there is an intricate relationship between endocrine and immune events in the NOD mouse. They also suggest that tissue-specific autoimmune reactions could arise from developmental phenomena taking place during fetal life in which ECM-immune cell interaction(s) may play a key role

Residual ß-cell function and microvascular complications in type 1 diabetic patients

To determine the influence of residual ß-cell function on retinopathy and microalbuminuria we measured basal C-peptide in 50 type 1 diabetic outpatients aged 24.96 + or - 7.14 years, with a duration of diabetes of 9.1 + or - 6.2 years. Forty-three patients (86 percent) with low C-peptide (<0.74 ng/ml) had longer duration of diabetes than 7 patients (14 percent) with high C-peptide (<0.74 ng/ml) (9 (2-34) vs 3 (1-10) years, P = 0.01) and a tendency to high glycated hemoglobin (HBA1) (8.8 (6-17.9) vs 7.7 (6.9-8.7)percent, P = 0.08). Nine patients (18 percent) had microalbuminuria (two out of three overnight urine samples with an albumin excretion rate (AER)> or - 20 and <200 µg/min) and 13 (26 percent) had background retinopathy. No association was found between low C-peptide, microalbuminuria and retinopathy and no difference in basal C-peptide was observed between microalbuminuric and normoalbuminuric patients (0.4 + or - 0.5 vs 0.19 + or - 0.22 ng/ml, P = 0.61) and between patients with or without retinopathy (0.4 + or - 0.6 vs 0.2 + or - 0.3 ng/ml, P = 0.43). Multiple regression analysis showed that duration of diabetes (r = 0.30, r2 = 0.09, P = 0.031) followed by HBA1 (r = 0.41, r2 = 0.17, P = 0.01) influenced basal C-peptide, and this duration of diabetes was the only variable affecting AER (r = 0.40, r2 = 0.16, P = 0.004). In our sample of type 1 diabetic patients residual ß-cell function was not associated with microalbuminuria or retinopathy

Serum Insulin, Proinsulin and Proinsulin/Insulin Ratio in Type 2 Diabetic Patients: As an Index of beta-Cell Function or Insulin Resistance

BACKGROUND: Although insulin resistance and decreased insulin secretion are characteristics of established type 2 DM, which of these metabolic abnormalities is the primary determinant of type 2 DM is controversial. It is also not well known how insulin resistance and beta cell dysfunction influence serum insulin, proinsulin, proinsulin/insulin ratio in type 2 DM. METHODS: We compared serum insulin, proinsulin and proinsulin/insulin ratio in type 2 diabetic patients and control subjects. We also investigated the relationship between serum insulin, proinsulin and proinsulin/insulin ratio and several biochemical markers which represent insulin resistance or beta cell function. RESULTS: Insulin, proinsulin and proinsulin/insulin ratio were significantly higher in type 2 DM than control(p < 0.001). In diabetic patients, total insulin level was correlated with urinary albumin excretion rates(r = 0.224, p = 0.025) and body mass index(r = 0.269, p = 0.014). Proinsulin level was correlated with fasting C-peptide(r = 0.43, p = 0.002), postprandial 2 hour blood glucose(r = 0.213, p = 0.05) and triglyceride(r = 0.28, p = 0.022). Proinsulin/insulin ratio was positively correlated with fasting C-peptide(r = 0.236, p = 0.031), fasting blood glucose (r = 0.264, p = 0.015), postprandial 2 hour blood glucose(r = 0.277, p = 0.001) and triglyceride(r = 0.428, p < 0.001). In control subjects, insulin level was correlated with triglyceride(r = 0.366, p = 0.002). Proinsulin/insulin ratio was correlated with age(r = 0.241, p = 0.044). CONCLUSION: The serum levels of insulin and proinsulin seem to be associated with several markers of insulin resistance. Whereas proinsulin/insulin ratio might represent beta cell function rather than insulin resistance. But more studies are needed to clarify the mechanisms of elevated proinsulin/insulin ratio in type 2 DM.

Freqüência de diabetes mellitus e hiperglicemia em mulheres chagásicas e näo chagásicas / Hyperglycemia and diabetes mellitus in chagasic and non-chagasic women

Estudo retrospectivo de 647 mulheres com idade >/= 40 anos, atendidas no Hospital Escola da FMTM, Uberaba-MG. As três sorologias para a doença de Chagas foram negativas nas controles (n = 285) e positivas nas chagásicas (n = 362), que foram classificadas nas formas indeterminada (n = 125), megas (n = 58) e cardíaca (n = 179). Diabetes mellitus foi definido por duas glicemias em jejum >/= 140mg/dl e hiperglicemia por glicemia em jejum > l10mg/dl. Os grupos foram comparados pelos testes do x², análise de variância, "t" de Student, Kruskal-Wallis e Mann-Whitney, considerando-se significativo p < 0,05. chagásicas e controles estavam pareadas quanto à idade, o índice de massa corporal e a cor. Diabetes mellitus foi mais freqüente na forma cardíaca (15,1 por cento) comparada com as controles (7,4 por cento), megas (7,4 por cento) e assintomáticas (5,6 por cento), o mesmo ocorrendo com a hiperglicemiÝa (37,4 por cento, 26,7 por cento, 25,9 por cento e 27,2 por cento, respectivamente), achados que estäo de acordo com possível desnervaçäo parassimpática causada pelo Trypanosoma cruzi e conseqüente predomínio da atividade simpática

Specific insulin and proinsulin in normal glucose tolerant first-degree relatives of NIDDM patients

In order to identify early abnormalities in non-insulin-dependent diabetes mellitus (NIDDM) we determined insulin (using an assay that does not cross-react with proinsulin) and proinsulin concentrations. The proinsulin/insulin ratio was used as an indicator of abnormal ß-cell function. The ratio of the first 30-min increase in insulin to glucose concentrations following the oral glucose tolerance test (OGTT; I30-0/G30-0) was taken as an indicator of insulin secretion. Insulin resistance (R) was evaluated by the homeostasis model assessment (HOMA) method. True insulin and proinsulin were measured during a 75-g OGTT in 35 individuals: 20 with normal glucose tolerance (NGT) and without diabetes among their first-degree relatives (FDR) served as controls, and 15 with NGT who were FDR of patients with NIDDM. The FDR group presented higher insulin (414 pmol/l vs 195 pmol/l; P = 0.04) and proinsulin levels (19.6 pmol/l vs 12.3 pmol/l; P = 0.03) post-glucose load than the control group. When these groups were stratified according to BMI, the obese FDR (N = 8) showed higher fasting and post-glucose insulin levels than the obese NGT (N = 9) (fasting: 64.8 pmol/l vs 7.8 pmol/l; P = 0.04, and 60 min post-glucose: 480.6 pmol/l vs 192 pmol/l; P = 0.01). Also, values for HOMA (R) were higher in the obese FDR compared to obese NGT (2.53 vs 0.30; P = 0.075). These results show that FDR of NIDDM patients have true hyperinsulinemia (which is not a consequence of cross-reactivity with proinsulin) and hyperproinsulinemia and no dysfunction of a qualitative nature in ß-cells

Low levels of sex hormone-binding globulin and hyperproinsulinemia as markers of increased pancreatic Beta-cell demand in men

Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic ß-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic ß-cell secretion in men with different body compositions. Eighteen young men (30.0 ± 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P<0.05), proinsulin (r = -0.47, P<0.05), C-peptide (r = -0.55, P<0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P<0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P<0.05). When subjects were divided into obese (BMI >28 kg/m2, N = 8) and nonobese (BMI £25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic ß-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic ß-cell demand

Antioxidants and pancreatic beta-cell function in malnourished infants a causal relationship

The study was carried out on 30 infants between 6 and 24 months of age. They were equally divided into age and sex matched three groups of normally growing infants, marasmus, and kwashiorkor cases. Fasting levels of blood glucose, C-peptide, zinc, and vitamins A, E, and C were estimated. Blood glucose and C-peptide levels were serially estimated 1/2 and 2 hours after IV administration of 10 ml/kg of glucose 10% given as a bolus. None of the malnourished cases developed fasting hypoglycemia. Malnourished infants showed a postprandial diabetic- like curve after IV glucose challenge test concomitant with inappropriate increase in C- peptide secretion. They had also a significantly lower C- peptide /glucose ratio than the normally growing infants. Malnourished cases had a lower serum levels of zinc, vitamins A, E, and C. The glucose intolerance- manifested by low C-peptide /glucose ratio- was more evident among kwashiorkor cases who had also significantly lower levels of serum zinc and vitamin A than cases of marasmus. We suggested an association between glucose intolerance, poor cell response to IV glucose challenge test and the low serum levels of the antioxidants- zinc, vitamins A, E, and C among malnourished infants especially kwashiorkor cases that showed significantly lower results

Disfunçäo pancreática endócrina e exócrina em etilistas assintomáticos / Endocrine and exocrine pancreatic dysfunction in asymptomatic alcoholics

O autor estudou a funçäo pancreática numa populaçäo de 131 etilistas assintomáticos e em 102 indivíduos sadios (controle). O estudo da funçäo pancreática exócrina realizado através de estímulo com secretina mais colecistocinina revelou, além do aumento de volumem hipersecreçäo de bicarbonato, proteínas totais e albumina no suco pancreático dos etilistas. A avaliaçäo da funçäo endócrina através de estímulo com glicose via oral e IV e arginina IV revelou glicemias normais e níveis diminuídos de insulina e peptídeo C séricos, indicando hipofunçäo das células beta do pâncreas. Estes achados caracterizam disfunçäo pancreática endócrina e exócrina em etilistas assintomáticos

Lean (underweight) NIDDM - peculiarities and differences in metabolic and hormonal status - a pilot study.

In the present series of 204 patients with NIDDM, 37 were lean and 35 obese. Mean FBG and HbA1C were significantly higher (P<0.02 and <0.01) in the former. Serum lipids such as total cholesterol (Tc) and triglycerides (Tg) were lower (P<0.05) in the lean while HDLc values were similar. Eight lean patients and 6 obese (Mean BMI : 15.7 vs.27.4) having similar age (48.0 vs 47.7 years) and mean duration of diabetes (4.6 vs 4.2 years) were subjected to the study of insulin and C-peptide status as well as beta cell reserve. The mean basal serum insulin (IRI) level was lower in the lean (15.3 vs. 28.9 mu u/ml ; P<0.05) while there was no statistical difference in the basal C-peptide values. Serum samples analysed 2 hours after 75 G of oral glucose and 1 mg I.V. glucagon (Novo) on two consecutive occasions for IRI and C-peptide responses revealed remarkable differences. The rise in IRI was significantly lower (p<0.01) in the lean after oral glucose and glucagon as compared to the obese. But the C-peptide values did not reveal significant difference suggesting similar reserve in beta cell function in both these groups of patients with NIDDM. The disparity between IRI and C-peptide levels observed was most likely due to excess extraction of insulin by the liver in lean-NIDDM, leading to lower peripheral levels. This phenomenon accounts for the occurrence of severe hyperglycemia inspite of good beta cell function in lean NIDDM.

Ketosis resistant diabetes of the young: a profile of its exocrine and endocrine pancreatic dysfunction.

A subset of insulin requiring diabetes in the young (IRDY) is ketosis resistant. Its pathogenesis and pathophysiology remain ill defined. The current study was done to evaluate the exocrine and endocrine dysfunction in ketosis resistant young diabetics. Fecal chymotrypsin (unit/G), basal & stimulated c-peptide levels (pmol/ml) and sonographic evaluation of the pancreas were done in 59 IRDY patients: 34 ketosis resistant (KR) and 24 ketosis prone (KP). Fecal chymotrypsin levels in KR (11.1 +/- 3.4) and KP (10.3 +/- 5.1) were lower than in controls (22.4 +/- 7.3) (P < 0.01). KR subjects had better endogenous insulin reserves than KP subjects: the basal and stimulated c-peptide levels in KR patients (0.12 & 0.17) were higher than in KP subjects (0.06 and 0.07) (P < 0.05). A strong correlation was noted between the exocrine and beta cell dysfunction in KR subjects (r = 0.7, P < 0.05). Pancreas was smaller in KR and KP patients than in controls (P < 0.05) on sonography. Thus the resistance to ketosis is a reflection of the better preserved beta cell reserves in the KR patients. Loss of the trophic effect of insulin and associated malnutrition is responsible for their exocrine dysfunction.