Rebecca J. Brown

Ingestion of Diet Soda Before a Glucose Load Augments Glucagon-Like Peptide-1 Secretion

OBJECTIVE The goal of this study was to determine the effect of artificial sweeteners on glucose, insulin, and glucagon-like peptide (GLP)-1 in humans. RESEARCH DESIGN AND METHODS For this study, 22 healthy volunteers (mean age 18.5 ± 4.2 years) underwent two 75-g oral glucose tolerance tests with frequent measurements of glucose, insulin, and GLP-1 for 180 min. Subjects drank 240 ml of diet soda or carbonated water, in randomized order, 10 min prior to the glucose load. RESULTS Glucose excursions were similar after ingestion of carbonated water and diet soda. Serum insulin levels tended to be higher after diet soda, without statistical significance. GLP-1 peak and area under the curve (AUC) were significantly higher with diet soda (AUC 24.0 ± 15.2 pmol/l per 180 min) versus carbonated water (AUC 16.2 ± 9.0 pmol/l per 180 min; P = 0.003). CONCLUSIONS Artificial sweeteners synergize with glucose to enhance GLP-1 release in humans. This increase in GLP-1 secretion may be mediated via stimulation of sweet-taste receptors on L-cells by artificial sweetener.

Artificial Sweeteners: A systematic review of metabolic effects in youth

Epidemiological data have demonstrated an association between artificial sweetener use and weight gain. Evidence of a causal relationship linking artificial sweetener use to weight gain and other metabolic health effects is limited. However, recent animal studies provide intriguing information that supports an active metabolic role of artificial sweeteners. This systematic review examines the current literature on artificial sweetener consumption in children and its health effects. Eighteen studies were identified. Data from large, epidemiologic studies support the existence of an association between artificially-sweetened beverage consumption and weight gain in children. Randomized controlled trials in children are very limited, and do not clearly demonstrate either beneficial or adverse metabolic effects of artificial sweeteners. Presently, there is no strong clinical evidence for causality regarding artificial sweetener use and metabolic health effects, but it is important to examine possible contributions of these common food additives to the global rise in pediatric obesity and diabetes.

Low-calorie sweetener consumption is increasing in the United States

BACKGROUND Low-calorie and no-calorie sweeteners (LCSs) have emerged as alternatives to added sugars. Research suggests that consumption among all Americans is increasing, yet it is unknown whether consumption trends differ among population subgroups. OBJECTIVE Our study aimed to assess recent national trends in LCS consumption among children and other demographic subgroups in the United States. DESIGN We used NHANES data collected in five 2-y cycles from 1999-2000 to 2007-2008. Consumption of foods and beverages with LCSs was estimated by using one 24-h dietary recall. Estimates of the proportion of the population consuming foods and beverages containing LCSs (prevalence of consumption) were weighted to obtain nationally representative results. Trends in prevalence of LCS consumption and mean intake of beverages sweetened with LCSs were tested by using chi-square tests for trend and F tests. RESULTS In 2007-2008, the percentage of children and adults consuming foods and beverages containing LCSs increased. The prevalence of consuming beverages with LCSs increased from 6.1% to 12.5% among children (P-trend < 0.0001) and from 18.7% to 24.1% among adults (P < 0.001). Increases in the prevalence of consumption of calorie-containing beverages with LCSs were observed among all weight, age, socioeconomic, and race-ethnicity subgroups in both children and adults. However, little change in consumption of no-calorie beverages with LCSs or LCS-containing foods was found. CONCLUSIONS The consumption of LCS-containing beverages has doubled among US children over the past decade. Further research is needed to understand the health effects of this trend.

The liver diseases of lipodystrophy: The long-term effect of leptin treatment

BACKGROUND & AIMS Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. METHODS This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N=50) and after leptin replacement (N=27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A1c and liver enzymes were measured at baseline and at the time of the final liver biopsy. RESULTS In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 ± 3.7 months (mean ± SE, p=0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score (p<0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. CONCLUSIONS The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients.

Non-Nutritive Sweeteners and their Role in the Gastrointestinal Tract

CONTEXT Non-nutritive sweeteners can bind to sweet-taste receptors present not only in the oral cavity, but also on enteroendocrine and pancreatic islet cells. Thus, these sweeteners may have biological activity by eliciting or inhibiting hormone secretion. Because consumption of non-nutritive sweeteners is common in the United States, understanding the physiological effects of these substances is of interest and importance. EVIDENCE ACQUISITION A PubMed (1960-2012) search was performed to identify articles examining the effects of non-nutritive sweeteners on gastrointestinal physiology and hormone secretion. EVIDENCE SYNTHESIS The majority of in vitro studies showed that non-nutritive sweeteners can elicit secretion of gut hormones such as glucagon-like peptide 1 and glucose-dependent insulinotropic peptide in enteroendocrine or islet cells. In rodents, non-nutritive sweeteners increased the rate of intestinal glucose absorption, but did not alter gut hormone secretion in the absence of glucose. Most studies in humans have not detected effects of non-nutritive sweeteners on gut hormones or glucose absorption. Of eight human studies, one showed increased glucose-stimulated glucagon-like peptide 1 secretion after diet soda consumption, and one showed decreased glucagon secretion after stevia ingestion. CONCLUSIONS In humans, few studies have examined the hormonal effects of non-nutritive sweeteners, and inconsistent results have been reported, with the majority not recapitulating in vitro data. Further research is needed to determine whether non-nutritive sweeteners have physiologically significant biological activity in humans.

Minocycline-Induced Drug Hypersensitivity Syndrome Followed by Multiple Autoimmune Sequelae

BACKGROUND Drug hypersensitivity syndrome (DHS) is a severe, multisystem adverse drug reaction that may occur following the use of numerous medications, including anticonvulsants, sulfonamides, and minocycline hydrochloride. Long-term autoimmune sequelae of DHS have been reported, including hypothyroidism. OBSERVATIONS A 15-year-old female adolescent developed DHS 4 weeks after starting minocycline therapy for acne vulgaris. Seven weeks later she developed autoimmune hyperthyroidism (Graves disease), and 7 months after discontinuing minocycline therapy she developed autoimmune type 1 diabetes mellitus. In addition, she developed elevated titers of several markers of systemic autoimmune disease, including antinuclear, anti-Sjögren syndrome A, and anti-Smith antibodies. CONCLUSIONS Minocycline-associated DHS may be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and elevated markers of systemic autoimmunity. Long-term follow-up is needed in patients with DHS to determine the natural history of DHS-associated sequelae.

Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes.

OBJECTIVE—To determine the time course of changes in glucagon and insulin secretion in children with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS—Glucagon and C-peptide concentrations were determined in response to standard mixed meals in 23 patients with type 1 diabetes aged 9.4 ± 4.6 years, beginning within 6 weeks of diagnosis, and every 3 months thereafter for 1 year. RESULTS—Glucagon secretion in response to a physiologic stimulus (mixed meal) increased by 37% over 12 months, while C-peptide secretion declined by 45%. Fasting glucagon concentrations remained within the normal (nondiabetic) reference range. CONCLUSIONS—Postprandial hyperglucagonemia worsens significantly during the first year after diagnosis of type 1 diabetes and may represent a distinct therapeutic target. Fasting glucagon values may underestimate the severity of hyperglucagonemia. The opposing directions of abnormal glucagon and C-peptide secretion over time support the link between dysregulated glucagon secretion and declining β-cell function.

Effects of Diet Soda on Gut Hormones in Youths With Diabetes

OBJECTIVE In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes. RESEARCH DESIGN AND METHODS Subjects aged 12–25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects. RESULTS GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group. CONCLUSIONS Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.

Effects of beta‐cell rest on beta‐cell function: a review of clinical and preclinical data

The concept of ‘β-cell rest’, or suppression of insulin release from β-cells, was originally developed in the context of type 1 diabetes mellitus. Clinicians noted that the initiation of insulin therapy in newly diagnosed patients often led to partial remission, the so-called ‘honeymoon period’, which is characterized by increased endogenous insulin secretion and reduced exogenous insulin requirements. This was first formally documented by Jackson et al. in 1940, who reported ‘a regimen of control designed to approximate normal conditions of metabolism’, which markedly decreased insulin requirements in children with type 1 diabetes (1). The first controlled clinical trial of β-cell rest was performed in the 1970’s, when Mirouze et al. reported increased ‘remission’ rates in patients treated with intensive vs. conventional insulin therapy (2). These and other observations generated the hypothesis that decreased demand on β-cells can improve insulin secretion and β-cell viability. This concept was subsequently expanded into the field of type 2 diabetes (3). In the context of this review, we use the term β-cell rest ‘inclusively’, meaning that the agents used to induce β-cell rest may have many additional beneficial effects on glucose metabolism beyond their direct action on β-cells. Most obvious is the case of exogenous insulin, which ameliorates glucotoxicity and simultaneously reduces endogenous insulin secretion – effects that are difficult to tease apart, especially in the clinical setting. Another important distinction is difficult or impossible to make in the clinical arena: whether improved β-cell function is observed because of more work performed by existing β-cells or by a greater number including new β-cells.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Significance The characterization of rare monogenic human disorders can and has yielded unique biological insights. Our phenotypic description and functional characterization of human loss-of-function mutations in PCYT1A is both clinically important for patients and their families afflicted with this rare but serious metabolic disease and biologically helpful in advancing understanding of the physiological consequences of impaired PCYT1A activity in humans. Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.