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A I Vinik

Publications and source records attributed to A I Vinik.

At least 19 recordsLinked to original sources
PubMed1996

Identification of differentially expressed genes induced in pancreatic islet neogenesis.

Cellophane wrapping of the hamster pancreas induces islet neogenesis. We have used the mRNA differential display technique to select for genes expressed during islet neogenesis but not in control pancreata. Ten candidate clones have been identified. Upon sequencing, 6 clones showed a high degree of homology to known genes, 1 showed some, and 3 showed no homology to genes of known sequence. Thus, mRNA differential display is a useful technique to identify genes induced during islet neogenesis, and in combination with screening hamster pancreatic cDNA libraries for full length clones, will enhance the likelihood of capturing the participants in this process.

Animals↗
PubMed1996

Prediabetic markers in children with stress hyperglycemia.

BACKGROUND: Previous studies have shown that children with stress hyperglycemia have an increased risk for development of type I or insulin-dependent diabetes mellitus. OBJECTIVE: To determine whether stress hyperglycemia in prospectively screened pediatric patients represents a prediabetic state. DESIGN: Prospective, cohort analytic study. SETTING: The Children's Hospital of the King's Daughters is an urban pediatric emergency department at a tertiary care, university-based children's hospital in Norfolk, Va. PATIENT POPULATION: All patients who required a venipuncture for evaluation of an acute illness or injury from October 1992 through March 1993 were screened prospectively for hyperglycemia (blood glucose level > or = 8.3 mmol/L [> or = 150 mg/dL]). Each hyperglycemic patient was age matched to a stress control subject (defined as a nonhyperglycemic but acutely ill child) from the emergency department and a healthy control subject from a well-child clinic. INTERVENTION: Blood samples were obtained at the time of initial evaluation in the emergency department from 30 hyperglycemic patients (age range, 4 weeks to 12.4 years; median, 2 years), 30 stress control subjects, and 30 healthy control subjects. All samples were tested for islet cell antibodies, insulin autoantibodies, glutamic acid decarboxylase (GAD) antibodies, and HLA typing, specifically the genotypes at the DQB1 gene. MAIN OUTCOME MEASURES: The presence of immunologic or genetic markers for insulin-dependent diabetes mellitus and/or the clinical development of insulin-dependent diabetes mellitus. RESULTS: No patients or control subjects were positive for islet cell antibodies. One hyperglycemic patient and 3 stress control subjects were positive for insulin autoantibodies; all 4 of these subjects had sickle-cell disease and fever. Four of the 8 patients with sickle-cell disease had insulin autoantibodies, compared with none of the 52 patients and stress control subjects without sickle-cell disease (P < .001). One healthy control subject had antibodies to GAD65. The patient group did not show increased genotypes at the DQB1 gene that were indicative of an enhanced risk for insulin-dependent diabetes mellitus. Of the 32 hyperglycemic patients, 27 healthy control subjects, and 25 stress control subjects contacted for follow-up at 31 to 36 months, none has developed insulin-dependent diabetes mellitus. CONCLUSIONS: Children with stress hyperglycemia do not have an increased prevalence of immunologic or genetic markers of insulin-dependent diabetes mellitus and thus do not appear to be at an increased risk for development of insulin-dependent diabetes mellitus. Our data suggest that insulin autoantibodies develop in children subject to sickle cell crises.

Acute Disease↗
PubMed1996

Islet-cell regeneration in the diabetic hamster pancreas with restoration of normoglycaemia can be induced by a local growth factor(s).

Partial pancreatic duct obstruction in the hamster leads to the induction of endocrine-cell differentiation and new islet formation. We prepared cytosolic extracts from the partially obstructed pancreas and identified one, which when administered i.p., produced significant increases in the incorporation of tritiated thymidine by ductular and islet cells, as well as a corresponding increase in islet mass. In this study, we evaluate the ability of this extract to reverse streptozotocin diabetes mellitus. Hamsters were treated i.p. twice daily for 7 weeks with either 0.9% NaCl (saline) (n = 10) or a cytosol extract (n = 10) prepared previously from partially obstructed hamster pancreata. All animals in the cytosol group survived vs only 60% of the saline group (p = 0.02). Random blood glucose levels were greater than 22.2 mmol/l in 90% of the saline group vs 40% in the cytosol group (p < 0.05). Pancreatic tissue from the surviving saline animals and from persistently hyperglycaemic cytosol-treated animals, showed intra-cytoplasmic vacuolation of islet cells, a characteristic lesion of sustained hyperglycaemic states. Vacuolation was not observed in normoglycaemic extract treated animals. Islets in hyperglycaemic animals demonstrated a profound decrease or absence of immunoreactive insulin, compared to an abundance of immunoreactive beta cells in cytosol-treated animals that reverted to normoglycaemia. In this group, single cells or nests of cells stained for insulin on glucagon cells were identified in ductal epithelium in association with cells budding from the duct. Morphometric analysis of pancreata in reverted cytosol-treated animals showed a new population of small islets compared with saline controls and an increased islet mass. In summary, streptozotocin diabetes can be reversed by new islet formation induced by local pancreatic growth factors, the exact nature of which remains to be determined.

Animals↗
PubMed1996

Induction of islet cell differentiation and new islet formation in the hamster--further support for a ductular origin.

Partial obstruction of the adult hamster pancreas leads to islet cell differentiation and new islet formation. From morphologic and morphometric observations, we have tentatively identified the source of the new islet tissue to be from cells in the ducts. In this study, in vivo labeling with a single pulse of tritiated thymidine after partial duct obstruction was used to ascertain whether newly formed islet cells were in fact derived from cells in the ductal epithelium. Supportive evidence for this formulation was also sought using immunocytochemistry for islet hormones and in situ hybridization for glucagon and insulin mRNA to probe areas of proliferating duct cells. Endocrine cell differentiation was observed as a migration of cells out from small ducts beginning at about 10 days after obstruction. Duct and islet cell labeling indices (LI;%) in control animals remained at a low level (0.25 +/- 0.01 and 0.26 +/- 0.03, respectively) throughout the experiment. In contrast, at 2 weeks after partial obstruction, the duct and islet cell LI were 4.2 +/- 0.7 and 0.80 +/- 0.1 (p < 0.05 vs. control). After 2 weeks, there was a rapid and significant 86% decline in the duct cell LI to a low of 0.6 +/- 0.2 at 8 weeks, which was accompanied by a comparable, but reciprocal, 113% increase in the islet cell LI to a high of 1.7 +/- 0.8 (p < 0.05). In situ hybridization demonstrated glucagon and insulin mRNA-positive cells within intralobular ducts as early as 6 and 8 days, respectively, after obstruction. Glucagon and insulin peptides appeared in these cells at approximately 8 and 10 days, respectively, as cells migrated out from the duct wall. This study provides additional evidence that further supports our concept that pancreatic endocrine cell differentiation in this model reiterates the normal ontogeny of beta cell differentiation from cells in the ductular epithelium.

Age Factors↗
PubMed1996

Endocrine tumors of the gastrointestinal tract.

Endocrine tumors of the gastrointestinal tract produce a variety of secretory products that cause unique clinical syndromes. Diagnosis, which is often delayed, requires a strong index of suspicion and must be confirmed by biochemical tests. Precisely where these tumors originate remains a topic of controversy. However, several growth factors that may be involved in tumor development have been identified, and genetic abnormalities in patients with multiple endocrine neoplasia have been described. New pre- and intraoperative localization techniques have greatly increased the ability to identify and resect these tumors. The long-acting somatostatin analogue octreotide is frequently useful as a tracer to localize tumors and as symptomatic therapy for limiting release of secretory products produced by the tumors. In some instances it may also have direct anti-tumor activity.

Carcinoid Tumor↗
PubMed1996

Impaired peripheral vasomotion in diabetes.

OBJECTIVE: To test the hypothesis that vasomotion, the rhythmic contraction exhibited by small arteries and arterioles, is impaired in diabetic subjects compared with healthy control subjects. RESEARCH DESIGN AND METHODS: We mathematically modeled the oscillations in laser Doppler microvascular measurements taken from the pulpar surface of the index finger in 20 healthy control subjects and 20 age-matched diabetic subjects (8 with type I and 12 with type II diabetes). The mean duration of diabetes was 17.1 +/- 2.3 years, and mean HbA1c was 9.1 +/- 0.4%. Blood flow was measured for 5 min as subjects rested quietly in a closed room. Fast Fourier transformation was performed to provide the frequency power spectrum of each recording. Amplitude of vasomotion was correlated with six quantitative measurements of neuropathy. RESULTS: Diabetic subjects had impaired low-frequency oscillation vasomotion in 75% of age-matched patients (15 of 20 patients), with mean amplitudes of 24.9 +/- 6.4 vs. 129.0 +/- 33.2 (P < 0.0039). Of six somatic and autonomic neuropathy variables, only the warm thermal sensory threshold correlated significantly with the mean amplitude of vasomotion (r = -0.75, P < 0.0009). CONCLUSIONS: Patterns of peripheral vasomotion are clearly disordered in diabetes. The loss of low-frequency oscillations observed here suggests a peripheral vascular abnormality that extends past the capillary network to arterial vessels. It is uncertain whether the accompanying small unmyelinated nerve C-fiber dysfunction is a cause or consequence of the impaired microvascular function. Measurement of vasomotion may prove useful as a novel test for peripheral neurovascular function.

Adolescent↗
PubMed1996

The natural progression of autonomic neuropathy and autonomic function tests in a cohort of people with IDDM.

OBJECTIVE: To test the natural progression of symptoms of autonomic neuropathy (AN) and function tests in subjects with IDDM. RESEARCH DESIGN AND METHODS: Seventy-six subjects with IDDM of < 10 years duration had cardiovascular autonomic reflex tests and were evaluated for signs and symptoms of AN. RESULTS: Fifty-seven subjects (66%) were available for restudy 9 years later (15 had died, 4 could not be located). Of the symptoms of AN, only gastroparesis increased in prevalence (P < 0.01). Of the five cardiovascular AN measures, only the R-R response to the Valsalva maneuver deteriorated (F[1,44] = 10.61, P < 0.01). CONCLUSIONS: The progression of AN in IDDM is monitored best longitudinally by the Valsalva maneuver because of the small variance ratio in repeated measures. Prevalence rates can be monitored by expiration-to-inspiration R-R or Valsalva ratios. Most clinical signs and symptoms of AN do not progress, underscoring the need for objective and quantitative autonomic function tests to identify people at risk for premature death.

Adolescent↗
PubMed1996

Paracrine/autocrine regulation of pancreatic islet cell proliferation and differentiation in the hamster: studies using parabiosis.

Partial obstruction of the pancreatic duct in hamsters leads to new islet formation and reversal of streptozotocin diabetes. The purpose of this study was to delineate the mechanism by which endocrine cell proliferation and differentiation is mediated in this model. Six pairs of parabiotic hamsters were established and partial duct obstruction was inducted in 1 parabiont from each pair. At 6 weeks, the pancreatic weight (mg/100g bw); DNA (microgram/100g bw) and protein content (mg/100g bw) showed 28% (167 +/- 21 vs. 130 +/- 17), 32% (1,052 +/- 206 vs. 795 +/- 159), and 20% (25.4 +/- 6.6 vs. 21.2 +/- 1.9) increases (p < 0.05), respectively, over the non-wrapped parabionts. Morphometric analysis demonstrated the presence of new islets in the wrapped pancreata with a 100% increase in the number of islets/mm2 compared with non-wrapped controls (0.90 +/- 0.5 vs. 1.8 +/- 0.7, p < 0.01). A cytosol extract was prepared from duct-obstructed pancreases, and 4 microliters/g bw injected i.p. twice daily for 2 d produced significant increases in pancreatic weight and DNA content of 12% and 40%, respectively. Cytosol extract from non-wrapped pancreata had no effects compared with saline. When wrapped cytosol extract was injected for 21 d, the labeling index of ductular and islet cells (% cell nuclei labeled with 3H-TdR) was increased 10- and 6-fold respectively over controls (2.42 +/- 0.28 vs. 0.23 +/- 0.01 and 1.17 +/- 0.01 vs. 0.25 +/- 0.04, respectively, p < 0.01). The trophic effects observed in this model of islet cell proliferation and differentiation did not appear to be mediated by a humoral mechanism because the changes induced by partial obstruction were not observed in the non-operated parabiont. Control of pancreatic endocrine cell growth in this model appears to involve paracrine and/or autocrine regulatory mechanisms.

Animals↗
PubMed1995

Quantitative measurement of cutaneous perception in diabetic neuropathy.

To determine the diagnostic value of various cutaneous sensory modalities in diabetic neuropathy, we studied cutaneous perception at the dominant hallux of 113 subjects (32 normal healthy controls and 81 diabetic subjects). The cutaneous sensory perception tests included warm and cold thermal perception, vibration, touch-pressure sensation, and current perception testing (CPT). The sensitivity of each modality when specificity is held greater than 90% was as follows: warm = 78%, cold = 77%, vibration = 88%, tactile-pressure = 77%, 5-Hz CPT = 52%, 250-Hz CPT = 48%, and 2000-Hz CPT = 56%. Combination thermal and vibratory gave optimum sensitivity (92-95%) and specificity (77-86%). We conclude that vibratory and thermal testing should be the primary screening tests for diabetic peripheral neuropathy. Other modalities may be of use only in specific situations.

Adult↗
PubMed1995

Up-regulation of laminin B2 gene expression in dorsal root ganglion neurons and nonneuronal cells during sciatic nerve regeneration.

A recent study in our laboratory showed that B2 laminin gene is expressed by all L4 and L5 dorsal root ganglion (DRG) neurons as well as by satellite and Schwann cells. Because the laminin B2 subunit has a domain that supports neurite extension in culture, the present study was undertaken to test the hypothesis that laminin B2 gene expression would increase during sciatic nerve regeneration. In situ hybridization was used to examine B2 laminin gene expression in L4 and L5 DRGs 28 days after creating and bridging a 10-mm sciatic nerve gap with an impermeable silicone tube. Overall there was a nearly threefold increase in DRG B2 laminin chain mRNA at this timepoint, a time when axons are known to show vigorous regrowth. Both neurons and nonneuronal cells contributed to this increase. These data suggest that an up-regulation of B2 laminin gene expression by DRG neurons and nonneuronal cells may play a role in peripheral nerve regeneration.

Animals↗
PubMed1995

Expression of Reg gene in the Syrian golden hamster pancreatic islet regeneration model.

We have reported previously that cellophane wrapping of the hamster pancreas is a stimulus that leads to the induction of duct epithelial cell proliferation, followed by endocrine cell differentiation and new islet formation. Reg is a candidate gene that has been reported to be expressed in regenerating pancreatic islets, suggesting a role in islet growth. We examined Reg gene expression in the cellophane-wrap model by isolating total RNA from hamster pancreata at various times after wrapping. Northern blot analysis using a rat cDNA Reg probe showed no expression of Reg in control non-wrapped hamster pancreas, whereas a strong signal was detected in control wrapped rat pancreas. Using reverse transcription of RNA followed by polymerase chain reaction (PCR) we amplified, isolated and sequenced a 194 base pair product which showed homology to rat Reg in both control and wrapped hamster pancreas. When the PCR product was used as a probe for Northern blot analysis, no signal was detected in control non-wrapped pancreata. In contrast, a strong signal was detected 1 and 2 days after wrapping, which then returned to basal between 4 and 6 days after wrapping. A similar temporal pattern was observed using in situ hybridization to localize the Reg gene. One- and 2-day wrapped but not control pancreas expressed Reg in acinar cells, but not in islets.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The neuronal toxic factor in serum of type 1 diabetic patients is a complement-fixing autoantibody.

Type 1 diabetes is an autoimmune disease resulting in destruction of pancreatic beta cells. Many of the pancreatic beta cell autoantigens are also neuronal cell components. Using adrenergic neuroblastoma cells, we have previously demonstrated that humoral mechanisms may contribute to the development of diabetic neuropathy in Type 1 patients. We hypothesize that the toxic factor in Type 1 diabetic serum is an immunoglobulin. When neuroblastoma cells were exposed to immunoglobulins precipitated from serum of Type 1 diabetes patients with neuropathy, cell growth was significantly inhibited by day 5 (3.8 +/- 2.4 x 10(5) cells) compared to cells cultured with immunoglobulins from control (8.2 +/- 2.3 x 10(5) cells) or Type 2 diabetic serum (7.0 +/- 3.0 x 10(5) cells). The inhibitory effect (3.2 +/- 0.9 x 10(5) cells) could be removed from Type 1 diabetic serum by affinity precipitation with protein A-agarose (8.0 +/- 0.8 x 10(5) cells). Mild heat denaturing of the serum reversed the inhibitory effect (3.8 +/- 0.9 vs 1.4 +/- 1.4 x 10(5) cells), indicating a requirement for complement. Immunofluorescent labelling with anti-IgG secondary antibody of cells exposed to Type 1 diabetic serum indicated recognition of a membrane-bound antigen. The studies in this report support the hypothesis that autoimmune neuronal destruction may contribute to the development of diabetic autonomic neuropathy in patients with Type 1 diabetes.

Adult↗
PubMed1995

Clinical review 72: diagnosis and management of functioning islet cell tumors.

Functional islet cell tumors cause recognizable clinical syndromes based on the peptide products they secrete (Table 1). Frequently, the diagnosis of these tumors is delayed. A high index of suspicion coupled with the use of appropriate biochemical and provocative tests should lead to earlier diagnosis. A suggested management plan for patients suspected of having an islet cell tumor is shown in Fig. 1. Earlier diagnosis coupled with advances in preoperative and intraoperative localization techniques have resulted in an increased number of patients being cured.

Adenoma, Islet Cell↗
PubMed1995

Beyond glycemia.

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Blood Glucose↗
PubMed1995

Phospholipid and glutamic acid decarboxylase autoantibodies in diabetic neuropathy.

OBJECTIVE: To determine the prevalence and significance of phospholipid autoantibodies (PLAs) and glutamic acid decarboxylase (GAD) autoantibodies in the circulation of normal patients and diabetic patients with and without neuropathy. RESEARCH DESIGN AND METHODS: We measured PLAs in a total of 78 patients (a diabetic group with somatic or autonomic neuropathy [n = 40] another group without neuropathy [n = 38]), and GAD autoantibodies in a subset of 22 patients. RESULTS: PLAs are found in 2% of the general population. We found PLAs in 32% of the diabetic population without neuropathy, in 88% of those with neuropathy, in 55% of those with retinopathy, and in 25% of those with established nephropathy. The frequencies of immunoglobulins in the neuropathic group were: IgG = 78%, IgM = 33%, and IgA = 23%. There was no correlation between PLAs and microalbuminuria, macrovascular disease, fibrinogen, duration of diabetes, or neuropathy, but there was a strong correlation with total neuropathy score. Sera with high PLA IgG titers bound to the surface of neuroblastoma cells and inhibited cell growth. Antibodies to GAD65 were present in 32% and to GAD67 in 0% of patients. No titers of GAD65, GAD67, or the GAD65 ratio were associated with the degree of neuropathy of the presence of PLAs. CONCLUSIONS: PLAs occur frequently in the sera of patients with diabetes and correlate with the extent of neuropathy, suggesting a role for PLAs in the etiology thereof. The measurement of PLAs may constitute a marker for ongoing damage to nerves.

Analysis of Variance↗
PubMed1994

Pentagastrin infusions in patients with panic disorder. II. Neuroendocrinology.

Cholecystokinin (CCK) has well-documented anxiogenic effects in animals and normal people, and panicogenic effects in patients with panic disorder, but little is known about its neuroendocrine profile. We examined neuroendocrine responses to intravenous infusions of pentagastrin, a selective CCK-B receptor agonist, in 10 patients with panic disorder and 10 normal control subjects. Pentagastrin potently activated the hypothalamic-pituitary-adrenal (HPA) axis, but did not release growth hormone or any of several vasoactive peptides (neurokinin A, substance P, vasoactive intestinal peptide). The HPA axis response was unrelated to increases in symptoms. Panic patients did not differ from controls in neuroendocrine responses to the CCK agonist. Differential sensitivity to novelty stress accounted for the only patient-control differences in neuroendocrine profiles. The data suggest that CCK may help modulate normal HPA axis activity, but its anxiogenic effects are unrelated to its stimulatory effects on the HPA axis. Pentagastrin provides a safe and readily available probe for further study of CCK receptor systems in humans.

Adrenocorticotropic Hormone↗
PubMed1994

Differential laminin gene expression in dorsal root ganglion neurons and nonneuronal cells.

Laminin is a substrate for cell migration and process outgrowth during development and may play an important role in peripheral nerve regeneration. While most studies have emphasized the expression and production of this glycoprotein by Schwann cells, in the current study we use in situ hybridization to examine the expression of the various laminin chain genes in neuronal as well as nonneuronal cells of normal adult rat lumbar dorsal root ganglia. Hybridization using cRNA probes derived from cDNAs encoding nonhomologous regions of each laminin chain showed differential localization of the chain messages within the ganglia. B2 chain mRNA was abundant in large and small neurons, satellite cells, and Schwann cells. B1 chain message was also localized in satellite and Schwann cells, but its neuronal expression was primarily restricted to a subpopulation of smaller neurons. Message encoding merosin M chain, an A chain variant, was localized within satellite cells and Schwann cells but was absent or of very low abundance in neurons. A chain mRNA was not detectable in any of the three nervous tissue cell types. The differential expression of the four laminin chains in the DRG is discussed in relation to the functional epitopes of the molecule.

Animals↗