Is type I diabetes a virus-induced disease?

The conditions are critically reviewed under which diseases might be aetiologically related to infection by a certain virus. Such a causal correlation has to obey Koch's postulates, but may be very difficult to prove in the case of a "hit and run" process. This will be exemplified in the case of insulin-dependent diabetes mellitus (IDDM). Observations in humans and the results of experiments on laboratory animals are reported, whereby the Coxsackie B and mumps viruses are of particular interest. Furthermore, the mechanisms by which viruses may produce autoimmune diseases are discussed, including virological and immunological aspects. The hypothesis of "molecular mimicry" by Oldstone is quoted as a unifying one, allowing the combination of both aspects. His main assumption is oligopeptide homology between certain virus proteins and some cell proteins and some examples are given. In the presence of such homologies the immune system is first stimulated by the parasitic virus protein, but somewhat later this reaction switches against the host structures, causing continuing cellular damage with the development of autoimmune disease. It is concluded that Koch's postulates in such cases have to be supplemented by assaying for amino acid homologies in viruses and certain cell types.     

Is pancreatic polypeptide response to food ingestion a reliable index of vagal function in type 1 diabetes?

OBJECTIVE: The diagnosis of autonomic neuropathy in diabetic patients is based on cardiovascular reflex tests. Since cardiac function may be affected by arteriosclerosis and cardiomyopathy in type 1 diabetes mellitus, alternative tests reflecting vagal nerve function, in other organ systems, are needed. In this study the pancreatic polypeptide (PP) response to a mixed meal was evaluated in healthy subjects and in recently diagnosed type 1 diabetic patients. MATERIAL AND METHODS: The PP response was studied at different levels of the vagally mediated reflex arch by application of different stimuli: meal ingestion, i.v. edrophonium (a cholinesterase inhibitor) injection and arginine infusion. RESULTS: Meal ingestion (stimulation of cerebral/vagal level) resulted in a significant and similar PP response in the two groups; i.v. edrophonium injection (stimulating at the second neuron level) resulted in a smaller increase in PP concentrations in the type 1 diabetic patients as compared with the healthy subjects, whereas direct PP-cell stimulation by arginine infusion resulted in similar increments in PP concentrations in the two groups. Thus, in recently diagnosed type 1 diabetic patients with no known manifestations of diabetic neuropathy, the cholinergic second neuron function of the vagal arch to the pancreas is impaired, whereas intrinsic PP-cell function is unaffected. CONCLUSIONS: This abnormality in cholinergic second neuron function of the vagal reflex arch and the fact that three of the healthy subjects had no increase in PP concentrations at all during the meal test indicates that PP response to a mixed meal is unsuitable for the diagnosis of autonomic neuropathy in type 1 diabetes. The nature of the defect in the second neuron of the vagal innervation of the pancreas in type 1 diabetes remains to be elucidated.     

Is HbA1c a good screening test for diabetes mellitus?

ObjectivesHbA_1c has been recently recommended as the primary diagnostic test for diabetes. This study evaluated the positive predictive value (PPV) and negative predictive value (NPV) of HbA_1c against the oral glucose tolerance test (OGTT) in three locations.Design and methodsThree years of data with concurrent OGTT and HbA_1c tests were extracted from Laboratory Information Systems (LIS) and receiver operator (ROC) curves and positive and negative predictive values calculated comparing the OGTT with the HbA_1c values using a 10% prevalence of diabetes.ResultsThe recommended threshold HbA_1c value of 6.5% did not give the optimal combination of NPV (0.93 to 0.92) and PPV (0.40 to 0.61) compared to a threshold HbA_1c value of 7.0% (NPV 0.91 to 0.92, PPV 0.61 to 0.73).ConclusionThe optimal HbA_1c value for the diagnosis of diabetes is 7.0% but even at this HbA_1c the PPV is suboptimal and may cause up to 12% of patients without diabetes, as defined by a normal OGTT, to be classified having diabetes mellitus.     

Is HbA(1c) affected by glycemic instability?

OBJECTIVE: HbA(1c) is a standard clinical assessment of glycemia and the basis of most data relating glycemic control to complications. It remains unclear, however, whether HbA(1c) is affected by glycemic variation and mean glycemia. RESEARCH DESIGN AND METHODS: To test this question, we analyzed the statistical relationship between HbA(1c) levels and glycemic variability as measured by self-monitoring of blood glucose (SMBG). The records of 256 subjects were studied. SMBG data for the preceding 3 months were downloaded, and HbA(1c) was measured by ion-exchange high-performance liquid chromatography. Simple- and random-effects linear regression models were used to assess the independent contributions of mean blood glucose (BG) and SD of BG to HbA(1c), after adjusting for the mean BG. RESULTS: Mean +/- SD for HbA(1c) was 7.66 +/- 1.11% and for BG was 8.5 +/- 1.9 mmol/l (153.3 +/- 34.9 mg/dl); SD of BG for individual subjects was 3.5 mmol/l (63.3 mg/dl), varying from 0.4 mmol/l (8.1 mg/dl; very stable glycemia) to 8.4 mmol/l (152.5 mg/dl; very unstable glycemia). A close correlation between mean BG and HbA(1c) was demonstrated (r = 0.62). Also, within-subject SD of BG correlated with HbA(1c) (r = 0.375), indicating that people with poorer glycemic control had higher BG variance. After adjusting for mean BG in a linear regression model, however, the effect of the within-subject SD of BG on the HbA(1c) was insignificant. Several further analyses confirmed the strength of the observation. CONCLUSIONS: HbA(1c) reflects mean glycemia and is not meaningfully affected by glycemic instability after adjusting for mean BG.     

Is there a role for gut microbiota in type 1 diabetes pathogenesis?

Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by insufficient insulin production due to the destruction of insulin secreting β-cells in the Langerhans islets. A variety of factors, including chemicals, viruses, commensal bacteria and diet have been proposed to contribute to the risk of developing the disorder. In the last years, gut microbiota has been proposed as a main factor in T1D pathogenesis. Several alterations of gut microbiota composition were described both in animal model and in humans. The decrease of Firmicutes/Bacteroides ratio was the most frequent pattern described, in particular, in human studies. Furthermore, Bacteroides, Clostridium cluster XIVa, Lactobacillus, Bifidobacterium, and Prevotella relative abundances were different in healthy and affected subjects. Dysbiosis would seem to increase intestinal permeability and thus promote the development of a pro-inflammatory niche that stimulates β-cell autoimmunity in predisposed subjects. Preliminary studies on animal models were realized to investigate the role of gut microbiota modulation as therapy or prevention approach in predisposed animals: promising and stimulating results have been reported.

• Key message

• Dietary antigens and microbiota-derived products might act as triggers of T1D by causing a pro-inflammatory and metabolic dysfunctional environment.

     

Buccal spray insulin (Oralgen) for type 2 diabetes: what evidence?

INTRODUCTION: The achievement of a good glycemic control and, in particular, the management of postprandial hyperglycemia represent the most significant treatment target for the management of diabetes. Multiple daily insulin injections are often still required to gain the treatment goals. Since the noncompliance with injected insulin therapy causes a slowdown in the process of glycemic compensation, novel non-injectable insulin formulations have been developed. Oral spray insulin (Oralgen) is a tasteless liquid formulation that provides insulin absorption via buccal mucosa. AREAS COVERED: To elucidate the current status of Oralgen in type 2 diabetes patients, studies of pharmacodynamic and pharmacokinetic and clinical trials are reviewed. EXPERT OPINION: The 'psychological insulin resistance,' represented by the reluctance of both patients and health-care professionals to initiate insulin therapy, could be won by alternative routes of insulin administration, improving patients' compliance. In particular, Oralgen seems to be suitable to manage the postprandial hyperglycemia without hypoglycemic risk, although no comparative studies with rapid-acting insulin analogs and no randomized controlled trials in large cohort subjects with type 2 diabetes are available to date.     

Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non‐autoimmune (type 2) diabetes

ObjectiveTo investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non‐autoimmune (type 2) diabetes in young adults. Material and methods Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15–34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody‐negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3–4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. Results Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2–3‐fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01–0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut‐off, the sensitivity and specificity for differentiation between autoimmune and non‐autoimmune diabetes were 87% and 92%, respectively. At 3–4 months after clinical onset of diabetes, proinsulin secretion was still 2–3 times higher in type 2 than in type 1 diabetes patients (p<0.001). Conclusions. Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non‐autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.     

Metabolic syndrome and type 2 diabetes: can we stop the weight gain with diabetes?

Many patients with type 2 diabetes also have the metabolic syndrome with its cardinal features of central adiposity, insulin resistance, dyslipidemia, and hypertension. Although there is strong evidence for the importance of tight glycemic control in minimizing the microvascular complications of diabetes, many of the current therapies used for optimizing glycemic control also cause weight gain. With this treatment-induced weight gain, there is a risk of worsening the patient's insulin resistance. Physicians need to be aware of this vicious cycle in their overweight type 2 diabetic patients. This article reviews the strategies currently available to achieve glycemic control while at the same time minimizing weight gain and the associated complications.     

Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis

Type 2 diabetes, which accounts for 90-95% of all cases of diabetes, is a growing epidemic that places a severe burden on health care systems, especially in developing countries. Because of both the scale of the problem and the current epidemic growth of diabetes, it is a priority to find new approaches to better understand and treat this disease. Gastrointestinal surgery may provide new opportunities in the fight against diabetes. Conventional gastrointestinal operations for morbid obesity have been shown to dramatically improve type 2 diabetes, resulting in normal blood glucose and glycosylated hemoglobin levels, with discontinuation of all diabetes-related medications. Return to euglycemia and normal insulin levels are observed within days after surgery, suggesting that weight loss alone cannot entirely explain why surgery improves diabetes. Recent experimental studies point toward the rearrangement of gastrointestinal anatomy as a primary mediator of the surgical control of diabetes, suggesting a role of the small bowel in the pathophysiology of the disease. This article presents available evidence in support of the hypothesis that type 2 diabetes may be an operable disease characterized by a component of intestinal dysfunction.