Insulin resistance is the best prediction factor for the clinical onset of type 2 diabetes. It was suggested that intramuscular triglyceride store may be a primary pathogenic factor for its development. To test this hypothesis, 14 young lean offspring of type 2 diabetic parents, a model of in vivo insulin resistance with increased risk to develop diabetes, and 14 healthy subjects matched for anthropomorphic parameters and life habits were studied with 1) euglycemic-hyperinsulinemic clamp to assess whole body insulin sensitivity, 2) localized 1H nuclear magnetic resonance (NMR) spectroscopy of the soleus (higher content of fiber type I, insulin sensitive) and tibialis anterior (higher content of fiber type IIb, less insulin sensitive) muscles to assess intramyocellular triglyceride content, 3) 13C NMR of the calf subcutaneous adipose tissue to assess composition in saturated/unsaturated carbons of triglyceride fatty acid chains, and 4) dual X-ray energy absorption to assess body composition. Offspring of diabetic parents, notwithstanding normal fat content and distribution, were characterized by insulin resistance and increased intramyocellular triglyceride content in the soleus (P < 0.01) but not in the tibialis anterior (P = 0.19), but showed a normal content of saturated/unsaturated carbons in the fatty acid chain of subcutaneous adipocytes. Stepwise regression analysis selected intramyocellular triglyceride soleus content and plasma free fatty acid levels as the main predictors of whole body insulin sensitivity. In conclusion, 1H and 13C NMR spectroscopy revealed intramyocellular abnormalities of lipid metabolism associated with whole body insulin resistance in subjects at high risk of developing diabetes, and might be useful tools for noninvasively monitoring these alterations in diabetes and prediabetic states.

The treatment of diabetes mellitus by transplantation of isolated pancreatic islets is an approach that remains the subject of research by a large number of investigators throughout the world. A crucial requirement for the success of this enterprise is the ability to prepare viable isolated islets in adequate quantity. Over the years numerous descriptions of procedures for islet isolation from the pancreas of experimental animals and of man have been advanced; each claiming to be an improvement on previous methods. Indeed, there certainly have been advances, although few techniques live up to the claims that are made in their support Part of the problem is the generally poor methodology

No diabetes physician would question the fact that problems relating to nerve damage in diabetes mellitus are extremely common and result in much patient morbidity and unhappiness [1]. However, as the cause and natural history of diabetic peripheral neuropathy remain unknown, attempts at defining minimal criteria for the presence of neuropathy have proved difficult [2]. This is probably the most important reason for the widely varied estimates of the prevalence of diabetic peripheral neuropathy. Other factors include differing patient selection criteria, the small size of cohorts and the employment of different diagnostic tests. Some studies have used the presence of neuropathic symptoms [3] alone for the diagnosis of neuropathy while others have used both symptoms and signs of neuropathy as minimal criteria for diagnosis [4,5]. The San Antonio Conference on Diabetic Neuropathy [6] recommended that for full classification of diabetic neuropathy, at least one measure from each of the following categories need Diabetologia (1996) Summary The EURODIAB IDDM Complications Study involved the examination of 3250 randomly selected insulin-dependent diabetic patients, from 31 centres in 16 European countries. Part of the examination included an assessment of neurological function including neuropathic symptoms and physical signs, vibration perception threshold, tests of autonomic function and the prevalence of impotence. The prevalence of diabetic neuropathy across Europe was 28 % with no significant geographical differences. Significant correlations were observed between the presence of diabetic peripheral neuropathy with age (p < 0.05), duration of diabetes (p < 0.001), quality of metabolic control (p < 0.001), height (p < 0.01), the presence of background or proliferative diabetic retinopathy (p < 0.01), cigarette smoking (p < 0.001), high-density lipoprotein cholesterol (p < 0.001) and the presence of cardiovascular disease (p < 0.05), thus confirming previous associations. New associations have been identified from this study -namely with elevated diastolic blood pressure (p < 0.05), the presence of severe ketoacidosis (p < 0.001), an increase in the levels of fasting triglyceride (p < 0.001), and the presence of microalbuminuria (p < 0.01). All the data were adjusted for age, duration of diabetes and HbA 1c . Although alcohol intake correlated with absence of leg reflexes and autonomic dysfunction, there was no overall association of alcohol consumption and neuropathy. The reported problems of impotence were extremely variable between centres, suggesting many cultural and attitudinal differences in the collection of such information in different European countries. In conclusion, this study has identified previously known and new potential risk factors for the development of diabetic peripheral neuropathy. [Diabetologia (1996[Diabetologia ( ) 39: 1377[Diabetologia ( -1384

Stiff-man syndrome is a rare disorder of the central nervous system of unknown pathogenesis. We have previously reported the presence of autoantibodies against glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, epilepsy, and insulin-dependent diabetes mellitus. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) and in pancreatic beta cells. We subsequently observed autoantibodies to GABA-ergic neurons in 20 of 33 patients with stiff-man syndrome. GAD was the principal autoantigen. In the group of patients positive for autoantibodies against GABA-ergic neurons, there was a striking association with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus. These findings support the hypothesis that stiff-man syndrome is an autoimmune disease and suggest that GAD is the primary autoantigen involved in stiff-man syndrome and the associated insulin-dependent diabetes mellitus. Our findings also indicate that autoantibodies directed against GABA-ergic neurons are a useful marker in the diagnosis of the disease.

Stiff-man syndrome is a rare disorder of the central nervous system consisting of progressive, fluctuating muscle rigidity with painful spasms. It is occasionally associated with endocrine disorders, including insulin-dependent diabetes, and with epilepsy. We investigated the possible existence of autoimmunity against the nervous system in a patient with stiff-man syndrome associated with epilepsy and Type I diabetes mellitus. Levels of IgG, which had an oligoclonal pattern, were elevated in the cerebrospinal fluid. The serum and the cerebrospinal fluid produced an identical, intense staining of all gray-matter regions when used to stain brain sections according to an indirect light-microscopical immunocytochemical procedure. The staining patterns were identical to those produced by antibodies to glutamic acid decarboxylase (the enzyme responsible for the synthesis of gamma-aminobutyric acid). A band comigrating with glutamic acid decarboxylase in sodium dodecyl sulfate-polyacrylamide gels appeared to be the only nervous-tissue antigen recognized by cerebrospinal fluid antibodies, and the predominant antigen recognized by serum antibodies. These findings support the idea that an impairment of neuronal pathways that operate through gamma-aminobutyric acid is involved in the pathogenesis of stiff-man syndrome, and they raise the possibility of an autoimmune pathogenesis.

Endothelial nitric oxide synthase (eNOS) variants were previously demonstrated in cardiovascular disease. To evaluate whether eNOS gene variants are associated with insulin resistance and type 2 diabetes, we evaluated polymorphisms in Exon7 (E298D), intron 18 (IVS18 ؉ 27A3 C), and intron 23 (IVS23 ؉ 10G3 T) in 159 type 2 diabetic patients without macrovascular complications and in 207 healthy control subjects. Samples for all hormonal and metabolic variables were obtained after an overnight fast. The D298 and IVS18 ؉ 27C alleles, but not the IVS23 ؉ 10G3 T variant, were significantly more frequent in type 2 diabetic patients than in control subjects. The two-and three-loci haplotype analysis showed that there is a statistically significant association between the eNOS variants and type 2 diabetes. No significant differences were observed in the clinical characteristics of type 2 diabetic patients according to genotypes (except for visceral obesity [waist-to-hip ratio], which was significantly more present in D298 homozygotes). Healthy control subjects homozygous for both D298 and IVS18 ؉ 27C presented higher insulin, C-peptide, and nitric oxide levels, as well as higher HOMA (homeostasis model assessment) values than the double wild-type homozygotes, with values superimposable on those found in type 2 diabetic patients. In conclusion, we described a significant association between eNOS gene polymorphisms and type 2 diabetes, suggesting a new genetic susceptibility factor for hyperinsulinemia, insulin resistance, and type 2 diabetes. Diabetes 52:1270 -1275, 2003 T ype 2 diabetes is associated with a marked increase in coronary heart disease (CHD) (1), and increased risk factors for CHD before the onset of type 2 diabetes have been shown in several populations (2,3). In addition, type 2 diabetic patients with clinical cardiovascular disease sustain a worse prognosis for survival than cardiovascular disease patients without diabetes (4). This seems correlated to the high atherogenic state already present in a prediabetic state, which might be partly related to insulin resistance (5).Recently, endothelial dysfunction, such as nitric oxide (NO) impairment, is regarded as an early step in the development of insulin resistance, atherosclerosis, and type 2 diabetes (6 -8). Studies evaluating the relation between CHD and endothelial dysfunction have clearly demonstrated that reduced NO-dependent endothelial vasodilation is an early functional disturbance in the development of atherosclerotic lesions (6 -8). In addition, among the many activities of NO, it has demonstrated its ability to modulate peripheral and hepatic glucose metabolism and insulin secretion, according to Pieper (9), who suggested that NO alterations play an important role in the evolution of insulin resistance and type 2 diabetes. Moreover, our group has found high NO levels and endothelial dysfunction in type 2 diabetic patients and first-degree relatives of subjects with type 2 diabetes (10), as well as in subjects with the insulin resistance syndrome...

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OBJECTIVE -The aim of this study was to evaluate whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine-3Ј,5Ј-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. RESEARCH DESIGN AND METHODS-A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into two groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo (orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemichyperinsulinemic clamp combined with [6, H 2 ]glucose infusion. A total of 10 normal subjects underwent the same test as control subjects.RESULTS -In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34%, whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal.CONCLUSIONS -L-Arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care 24:875-880, 2001C ontradictory results have been found concerning the influence of insulin on nitric oxide (NO), a potent molecule with vasodilatory function. Baron et al. (1,2) showed that insulinmediated vasodilation is largely dependent on the action of insulin on NO release, whereas Petrie et al. (3) have shown that endothelial NO synthesis and insulin sensitivity are positively correlated in healthy individuals. In addition, in obese patients and patients with type 2 diabetes, the insulin-mediated vasodilatory response seems blunted (4). However, Yki-Jarvinen et al. (5) were unable to find any correlation between insulin action and increment in blood flow in normal and obese subjects, although all agree that methacoline-induced vasodilation is impaired in insulin-resistant subjects.L-Arginine is a precursor for NO, and both in vitro and in vivo studies have demonstrated that L-arginine can augment vascular dilation under certain conditions (6). Experimental studies in cholesterol-fed rabbits have shown that dietary supplementation with L-arginine causes attenuation of endothelial dysfunction with increased NO activity, resulting in reduced platelet activation (7), monocyte adhesion (8), and a marked reduction in aortic and coronary atherosclerosis (9). Moreover, in young hypercholesterolemic adults, the administr...