Effect of short-term intensive insulin therapy on α-cell function in patients with newly diagnosed type 2 diabetes.

The effect of intensive insulin therapy on hyperglucagonemia in newly diagnosed type 2 diabetes (T2DM), and its associations with ß-cell function, has not been elucidated. This study assessed the effect of 12 weeks of intensive insulin therapy on hyperglucagonemia in newly diagnosed T2DM and its associations with ß-cell function, with reference to the effects of 12 weeks of oral hypoglycemic agents (OHAs).One hundred eight patients with newly diagnosed T2DM were enrolled from January 2015 to December 2015. The patients were randomly divided to receive, for 12 weeks, either intensive insulin therapy or OHAs. Meal tolerance tests were conducted at baseline before treatment (0 week), at 12 weeks (end of treatment), and 12 months after the initiation of treatment. The levels of glucagon, proinsulin, C-peptide (CP), and blood glucose were measured at timepoints 0, 30, and 120 minutes during the meal tolerance test.Intensive insulin treatment was associated with a decrease in glucagon levels (at 0, 30, and 120 minutes) and proinsulin/CP, and an increase in the insulin-secretion index ΔCP30/ΔG30 and ΔCP120/ΔG120, at 12 weeks and 12 months during the follow-up, compared with the corresponding effects of OHAs. Intensive insulin therapy could reduce but failed to normalize glucagon levels at 12 weeks. There were no correlations between the change of percentages in total area under the curve of glucagon and other glycemic parameters (proinsulin/CP; ΔCP30/ΔG30; or ΔCP120/ΔG120). Patients who received intensive insulin therapy were more likely to achieve their target glycemic goal and remission, compared with those who received OHAs.Short-term intensive insulin therapy facilitates the improvement of both ß-cell and α-cell function in newly diagnosed T2DM mellitus. Decline of ß-cell secretion and concomitant α-cell dysfunction may both be involved in the pathogenesis of T2DM.

Breath Hydrogen as a Biomarker for Glucose Malabsorption after Roux-en-Y Gastric Bypass Surgery.

OBJECTIVE: Abdominal symptoms are common after bariatric surgery, and these individuals commonly have upper gut bacterial overgrowth, a known cause of malabsorption. Breath hydrogen determination after oral glucose is a safe and inexpensive test for malabsorption. This study is designed to investigate breath hydrogen levels after oral glucose in symptomatic individuals who had undergone Roux-en-Y gastric bypass surgery. METHODS: This is a retrospective study of individuals (n = 63; 60 females; 3 males; mean age 49 years) who had gastric bypass surgery and then glucose breath testing to evaluate abdominal symptoms. RESULTS: Among 63 postoperative individuals, 51 (81%) had a late rise (≥45 minutes) in breath hydrogen or methane, supporting glucose malabsorption; 46 (90%) of these 51 subjects also had an early rise (≤30 minutes) in breath hydrogen or methane supporting upper gut bacterial overgrowth. Glucose malabsorption was more frequent in subjects with upper gut bacterial overgrowth compared to subjects with no evidence for bacterial overgrowth (P < 0.001). CONCLUSION: These data support the presence of intestinal glucose malabsorption associated with upper gut bacterial overgrowth in individuals with abdominal symptoms after gastric bypass surgery. Breath hydrogen testing after oral glucose should be considered to evaluate potential malabsorption in symptomatic, postoperative individuals.

[Malabsorption of fermentable oligo-, di-, or monosaccharides and polyols (FODMAP) as a common cause of unclear abdominal discomfort]. / Kohlenhydratmalabsorption: Unverträglichkeit fermentierbarer Oligo-, Di-, Monosaccharide und Polyole (FODMAP) als häufige Ursache unklarer abdomineller Beschwerden.

Carbohydrate malabsorption is a frequent but underestimated cause of unexplained gastrointestinal symptoms like meteorism, flatulence, pain and diarrhea. By means of hydrogen and/or methane breath test after ingestion of the respective carbohydrate it can be identified and diagnosed easily, fast and reliably by successful nutritional therapy. Besides the well known complaints caused by lactose and fructose malabsorption, other fermentable oligo-, di-, or monosaccharides and polyols (akronym: FODMAP) can cause abdominal discomfort and IBS-like symptoms. In addition to lactose (dairy products) and fructose (apples, pears, mango, watermelon), FODMAPs comprise galactans (legumes), fructans (wheat, onions, garlic, artichoke) and the artificial sweeteners sorbitol, mannitol, maltitol and xylitol (sugar free candy, light products). A general restriction of all FODMAP components can be beneficial in relieving symptoms and improving quality of life in patients with functional gastrointestinal complaints.

Occurrence of GLUT1 deficiency syndrome in patients treated with ketogenic diet.

Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy caused by a mutation in the SLC2A1 gene. This mutation causes a compromised transport of glucose across the blood-brain barrier. The treatment of choice is ketogenic diet, with which most patients become seizure-free. At the National Centre for Epilepsy, we have, since 2005, offered treatment with ketogenic diet (KD) and modified Atkins diet (MAD) to children with difficult-to-treat epilepsy. As we believe many children with GLUT1-DS are unrecognized, the aim of this study was to search for patients with GLUT1-DS among those who had been responders (>50% reduction in seizure frequency) to KD or MAD. Of the 130 children included, 58 (44%) were defined as responders. Among these, 11 were already diagnosed with GLUT1-DS. No mutations in the SLC2A1 gene were detected in the remaining patients. However, the clinical features of these patients differed considerably from the patients diagnosed with GLUT1-DS. While 9 out of 10 patients with GLUT1-DS became seizure-free with dietary treatment, only 3 out of the 33 remaining patients were seizure-free with KD or MAD treatment. We therefore conclude that a seizure reduction of >50% following dietary treatment is not a suitable criterion for identifying patients with GLUT1-DS, as these patients generally achieve complete seizure freedom shortly after diet initiation.

The role of fructose transporters in diseases linked to excessive fructose intake.

Fructose intake has increased dramatically since humans were hunter-gatherers, probably outpacing the capacity of human evolution to make physiologically healthy adaptations. Epidemiological data indicate that this increasing trend continued until recently. Excessive intakes that chronically increase portal and peripheral blood fructose concentrations to >1 and 0.1 mm, respectively, are now associated with numerous diseases and syndromes. The role of the fructose transporters GLUT5 and GLUT2 in causing, contributing to or exacerbating these diseases is not well known. GLUT5 expression seems extremely low in neonatal intestines, and limited absorptive capacities for fructose may explain the high incidence of malabsorption in infants and cause problems in adults unable to upregulate GLUT5 levels to match fructose concentrations in the diet. GLUT5- and GLUT2-mediated fructose effects on intestinal electrolyte transporters, hepatic uric acid metabolism, as well as renal and cardiomyocyte function, may play a role in fructose-induced hypertension. Likewise, GLUT2 may contribute to the development of non-alcoholic fatty liver disease by facilitating the uptake of fructose. Finally, GLUT5 may play a role in the atypical growth of certain cancers and fat tissues. We also highlight research areas that should yield information needed to better understand the role of these GLUTs in fructose-induced diseases.

The whey fermentation product malleable protein matrix decreases TAG concentrations in patients with the metabolic syndrome: a randomised placebo-controlled trial.

Animal and human studies suggest that a malleable protein matrix (MPM) from whey decreases plasma lipid concentrations and may positively influence other components of the metabolic syndrome such as glucose metabolism and blood pressure (BP). The primary objective of this double-blind, multi-centre trial was to investigate the effects of a low-fat yoghurt supplemented with whey MPM on fasting TAG concentrations in patients with the metabolic syndrome. A total of 197 patients were randomised to receive MPM or a matching placebo yoghurt identical in protein content (15 g/d). Patients were treated during 3 months with two daily servings of 150 g yoghurt each to compare changes from baseline in efficacy variables. MPM treatment resulted in a significantly larger reduction of TAG concentrations in comparison to placebo (relative change -16%, P=0·004). The difference was even more pronounced in subjects with elevated fasting TAG (≥200 mg/dl) at baseline (-18%, P=0·005). The relative treatment difference in fasting plasma glucose was -7·1 mg/dl (P=0·089). This effect was also more pronounced in subjects with impaired fasting glucose at baseline (-11 mg/dl, P=0·03). In patients with hypertension, the relative treatment difference in systolic BP reached -5·9 mmHg (P=0·054). The relative treatment difference in body weight was -1·7 kg (P=0·015). The most common adverse events were gastrointestinal in nature. Conclusions from the present study are that consumption of a low-fat yoghurt supplemented with whey MPM twice a day over 3 months significantly reduces fasting TAG concentrations in patients with the metabolic syndrome and improves multiple other cardiovascular risk factors.

Vitamin D, insulin secretion, sensitivity, and lipids: results from a case-control study and a randomized controlled trial using hyperglycemic clamp technique.

OBJECTIVE: Vitamin D deficiency is associated with an unfavorable metabolic profile in observational studies. The intention was to compare insulin sensitivity (the primary end point) and secretion and lipids in subjects with low and high serum 25(OH)D (25-hydroxyvitamin D) levels and to assess the effect of vitamin D supplementation on the same outcomes among the participants with low serum 25(OH)D levels. RESEARCH DESIGN AND METHODS: Participants were recruited from a population-based study (the Tromsø Study) based on their serum 25(OH)D measurements. A 3-h hyperglycemic clamp was performed, and the participants with low serum 25(OH)D levels were thereafter randomized to receive capsules of 20,000 IU vitamin D(3) or identical-looking placebo twice weekly for 6 months. A final hyperglycemic clamp was then performed. RESULTS: The 52 participants with high serum 25(OH)D levels (85.6 ± 13.5 nmol/L [mean ± SD]) had significantly higher insulin sensitivity index (ISI) and lower HbA(1c) and triglycerides (TGs) than the 108 participants with low serum 25(OH)D (40.3 ± 12.8 nmol/L), but the differences in ISI and TGs were not significant after adjustments. After supplementation, serum 25(OH)D was 142.7 ± 25.7 and 42.9 ± 17.3 nmol/L in 49 of 51 completing participants randomized to vitamin D and 45 of 53 randomized to placebo, respectively. At the end of the study, there were no statistically significant differences in the outcome variables between the two groups. CONCLUSIONS: Vitamin D supplementation to apparently healthy subjects with insufficient serum 25(OH)D levels does not improve insulin sensitivity or secretion or serum lipid profile.

Genetic syndromes of severe insulin resistance.

Insulin resistance is among the most prevalent endocrine derangements in the world, and it is closely associated with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease, and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and poses severe challenges in clinical management. However, the clinical disorders produced by different genetic defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This means that optimal management of affected patients should take into account the specific natural history of each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology.

Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation.

Processing of the glycan structures on glycoproteins by different glycosylation enzymes depends on, among other, the non-uniform distribution of these enzymes within the Golgi stacks. This compartmentalization is achieved by a balance between anterograde and retrograde vesicular trafficking. If the balance is disturbed, the glycosylation machinery is mislocalized, which can cause Congenital Disorders of Glycosylation type II (CDG-II), as illustrated by the identification of congenital defects in the Conserved Oligomeric Golgi (COG) complex in humans. We collected findings from different COG deficient cell types, such as CHO, yeast and human fibroblasts to hypothesize about structure and function of the COG complex, and compared the phenotypes and genotypes of the patients known with a COG deficiency. Among 35 CDG-II patients we found 5 patients with a COG defect. COG defects are a novel group of CDG-II with deficient N- as well as O-glycosylation.

Seizures, ataxia, developmental delay and the general paediatrician: glucose transporter 1 deficiency syndrome.

AIM: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4). METHODS: This is a review of eight Queensland patients with GLUT1-DS. The clinical presentation, clinical course, laboratory investigations and treatment outcomes are discussed. RESULTS: The clinical features noted in our patient cohort include combinations of ataxia, developmental delay and a severe seizure disorder that is refractory to anticonvulsant medications. Seizures are the most common clinical manifestation and may be exacerbated by phenobarbitone. The paired CSF: plasma glucose results ranged from 0.2 to 0.39 (normal <0.6) with an average of 0.33. 3-O-Methyl-D-Glucose uptake and GLUT1 Genotyping analysis have been performed on five patients thus far. Rapid and impressive seizure control was observed in 100% of our patients once the ketogenic diet was instituted, with half of the cohort being able to wean completely from anticonvulsants. CONCLUSION: Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.

Congenital disorders of glycosylation: glycosylation defects in man and biological models for their study.

Several inherited disorders affecting the biosynthetic pathways of N-glycans have been discovered during the past years. This review summarizes the current knowledge in this rapidly expanding field and covers the molecular bases of these disorders as well as their phenotypical consequences.