Successful Treatment of Postprandial Hyperinsulinemic Hypoglycemia After Billroth-II Gastrojejunostomy Using Octreotide.

Postprandial hyperinsulinemic hypoglycemia, although rare, is a well-documented complication that can manifest after upper gastrointestinal surgery. Despite its potential for severe morbidity, the underlying pathogenesis and optimal treatment strategies for this condition remain insufficiently understood. This report presents a compelling case of postprandial hypoglycemia following Billroth-II gastrojejunostomy, characterized by a marked increase in postprandial insulin levels, accompanied by the exaggerated response of incretin hormones. The incretin effect in this patient was found to be exceptionally high, measuring at approximately 90%. While nutritional interventions proved ineffective in alleviating the patient's symptoms, the administration of octreotide significantly attenuated the exaggerated postprandial insulin and incretin response, substantially ameliorating both the symptoms and postprandial hypoglycemia. Monthly subcutaneous injections of long-acting repeatable octreotide were initiated, resulting in the complete resolution of symptomatic postprandial hypoglycemia. Although the patient developed acalculous cholecystitis and gallstone cholangitis 2 years after commencing octreotide therapy, she has remained free from symptomatic postprandial hypoglycemia for more than 4 years. Our case underscores the efficacy of somatostatin analogs in the management of postprandial hyperinsulinemia after gastrointestinal surgery, shedding light on the potential involvement of incretin hormones in the pathophysiology of this condition.

Different sites of actions make different responses to thiazolidinediones between mouse and rat models of fatty liver.

Therapeutic approach for NAFLD is limited and there are no approved drugs. Pioglitazone (PGZ), a thiazolidinedione (TZD) that acts via peroxisome proliferator activated receptor gamma (PPARγ) is the only agent that has shown consistent benefit and efficacy in clinical trials. However, the mechanism of its therapeutic effect on NAFLD remains unclear. The poor understanding may be due to problems with mouse, a species most used for animal experiments. TZDs exacerbate fatty liver in mouse models while they improve it in rat models like in human patients. Therefore, we compared the effects of TZDs including PGZ and rosiglitazone (RGZ) in ob/ob mice and Lepmkyo/Lepmkyo rats, models of leptin-deficient obesity, and A-ZIP/F-1 mice and seipin knockout (SKO) rats, models of generalized lipodystrophy. Pparg mRNA expression was markedly upregulated in fatty livers of mouse models while it was unchanged in rat models. TZDs exacerbated fatty liver in ob/ob and A-ZIP/F-1 mice, improved it in Lepmkyo/Lepmkyo rats and showed no effect in SKO rats. Gene expression analyses of Pparg and its target gene, Fsp27 revealed that PPARγ in the adipose tissue is the exclusive therapeutic target of TZDs in rats but PPARγ in the liver in addition to the adipose tissue is also a major site of actions for TZDs in mice. Although the response to TZDs in mice is the complete opposite of that in human patients, no report has pointed out the problem with TZD studies using mouse models so far. The present study might provide useful suggestions in research on TZDs.

First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications.

CONTEXT: The PDX1 gene encodes pancreatic and duodenal homeobox, a critical transcription factor for pancreatic ß-cell differentiation and maintenance of mature ß-cells. Heterozygous loss-of-function mutations cause PDX1-MODY (MODY4). CASE DESCRIPTION: Our patient is an 18-year-old lean man who developed diabetes at 16 years of age. Given his early-onset age and leanness, we performed genetic testing. Targeted next-generation sequencing and subsequent Sanger sequencing detected a novel heterozygous frameshift mutation (NM_00209.4:c.218delT. NP_000200.1: p.Leu73Profs*50) in the PDX1 transactivation domain that resulted in loss-of-function and was validated by an in vitro functional study. The proband and his 56-year-old father, who had the same mutation, both showed markedly reduced insulin and gastric inhibitory polypeptide (GIP) secretion compared with the dizygotic twin sister, who was negative for the mutation and had normal glucose tolerance. The proband responded well to sitagliptin, suggesting its utility as a treatment option. Notably, the proband and his father showed intriguing phenotypic differences: the proband had been lean for his entire life but developed early-onset diabetes requiring an antihyperglycemic agent. In contrast, his father was overweight, developed diabetes much later in life, and did not require medication, suggesting the oligogenic nature of PDX1-MODY. A review of all reported cases of PDX1-MODY also showed heterogeneous phenotypes regarding onset age, obesity, and treatment, even in the presence of the same mutation. CONCLUSIONS: We identified the first Japanese family with PDX1-MODY. The similarities and differences found among the cases highlight the wide phenotypic spectrum of PDX1-MODY.

Facilitating screening of Klinefelter syndrome among patients with diabetes.

Klinefelter syndrome (KS) is frequently complicated by diabetes. However, it is severely underdiagnosed due to a lack of reliable screening methods. We diagnosed two patients with KS at the Center for Diabetes and Endocrinology, Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan. By comparing the patients with 39 non-KS patients with diabetes, we propose a screening tool for KS in patients with diabetes.

"Switched" metabolic acidosis in mitochondrial diabetes mellitus.

A patient with mitochondrial diabetes mellitus developed diabetic ketoacidosis. During insulin treatment, although diabetic ketoacidosis improved, lactic acidosis unexpectedly worsened. This clinical course, named "switched metabolic acidosis," could reflect the unique pathophysiology of the mitochondrial disorder.

The hepatokine FGF21 is crucial for peroxisome proliferator-activated receptor-α agonist-induced amelioration of metabolic disorders in obese mice.

Obesity causes excess fat accumulation in white adipose tissues (WAT) and also in other insulin-responsive organs such as the skeletal muscle, increasing the risk for insulin resistance, which can lead to obesity-related metabolic disorders. Peroxisome proliferator-activated receptor-α (PPARα) is a master regulator of fatty acid oxidation whose activator is known to improve hyperlipidemia. However, the molecular mechanisms underlying PPARα activator-mediated reduction in adiposity and improvement of metabolic disorders are largely unknown. In this study we investigated the effects of PPARα agonist (fenofibrate) on glucose metabolism dysfunction in obese mice. Fenofibrate treatment reduced adiposity and attenuated obesity-induced dysfunctions of glucose metabolism in obese mice fed a high-fat diet. However, fenofibrate treatment did not improve glucose metabolism in lipodystrophic A-Zip/F1 mice, suggesting that adipose tissue is important for the fenofibrate-mediated amelioration of glucose metabolism, although skeletal muscle actions could not be completely excluded. Moreover, we investigated the role of the hepatokine fibroblast growth factor 21 (FGF21), which regulates energy metabolism in adipose tissue. In WAT of WT mice, but not of FGF21-deficient mice, fenofibrate enhanced the expression of genes related to brown adipocyte functions, such as Ucp1, Pgc1a, and Cpt1b Fenofibrate increased energy expenditure and attenuated obesity, whole body insulin resistance, and adipocyte dysfunctions in WAT in high-fat-diet-fed WT mice but not in FGF21-deficient mice. These findings indicate that FGF21 is crucial for the fenofibrate-mediated improvement of whole body glucose metabolism in obese mice via the amelioration of WAT dysfunctions.

Fat Mass Reduction With Adipocyte Hypertrophy and Insulin Resistance in Heterozygous PPARγ Mutant Rats.

Agonist-induced activation of peroxisome proliferator-activated receptor-γ (PPARγ) stimulates adipocyte differentiation and insulin sensitivity. Patients with heterozygous PPARγ dominant-negative mutation develop partial lipodystrophy and insulin resistance. Inconsistent with this evidence in humans, it was reported that heterozygous PPARγ knockout mice have increased insulin sensitivity and that mice with heterozygous PPARγ dominant-negative mutation have normal insulin sensitivity and improved glucose tolerance. In the context of the interspecies intranslatability of PPARγ-related findings, we generated a PPARγ mutant rat with a loss-of-function mutation (Pparg(mkyo)) without dominant-negative activity by using the ENU (N-ethyl-N-nitrosourea) mutagenesis method. Heterozygous Pparg(mkyo/+) rats showed reduced fat mass with adipocyte hypertrophy and insulin resistance, which were highly predictable from known actions of PPARγ agonists and phenotypes of patients with the PPARγ mutation. This report is the first in our knowledge to clearly demonstrate that both alleles of PPARγ are required for normal adipocyte development and insulin sensitivity in vivo. Furthermore, the study indicates that PPARγ regulates mainly adipocyte number rather than adipocyte size in vivo. The choice of appropriate species as experimental models is critical, especially for the study of PPARγ.

Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis.

Seipin, encoded by BSCL2 gene, is a protein whose physiological functions remain unclear. Mutations of BSCL2 cause the most-severe form of congenital generalized lipodystrophy (CGL). BSCL2 mRNA is highly expressed in the brain and testis in addition to the adipose tissue in human, suggesting physiological roles of seipin in non-adipose tissues. Since we found BSCL2 mRNA expression pattern among organs in rat is similar to human while it is not highly expressed in mouse brain, we generated a Bscl2/seipin knockout (SKO) rat using the method with ENU (N-ethyl-N-nitrosourea) mutagenesis. SKO rats showed total lack of white adipose tissues including mechanical fat such as bone marrow and retro-orbital fats, while physiologically functional brown adipose tissue was preserved. Besides the lipodystrophic phenotypes, SKO rats showed impairment of spatial working memory with brain weight reduction and infertility with azoospermia. We confirmed reduction of brain volume and number of sperm in human patients with BSCL2 mutation. This is the first report demonstrating that seipin is necessary for normal brain development and spermatogenesis in addition to white adipose tissue development.

Leptin restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet.

Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair ß-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired ß-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 µg·kg⁻¹·day⁻¹) and/or exenatide (20 µg·kg⁻¹·day⁻¹) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity.

Generation of leptin-deficient Lepmkyo/Lepmkyo rats and identification of leptin-responsive genes in the liver.

Leptin is one of the key molecules in maintaining energy homeostasis. Although genetically leptin-deficient Lep(ob)/Lep(ob) mice have greatly contributed to elucidating leptin physiology, the use of more than one species can improve the accuracy of analysis results. Using the N-ethyl-N-nitrosourea mutagenesis method, we generated a leptin-deficient Lep(mkyo)/Lep(mkyo) rat that had a nonsense mutation (Q92X) in leptin gene. Lep(mkyo)/Lep(mkyo) rats showed obese phenotypes including severe fatty liver, which were comparable to Lep(ob)/Lep(ob) mice. To identify genes that respond to leptin in the liver, we performed microarray analysis with Lep(mkyo)/Lep(mkyo) rats and Lep(ob)/Lep(ob) mice. We sorted out genes whose expression levels in the liver of Lep(mkyo)/Lep(mkyo) rats were changed from wild-type (WT) rats and were reversed toward WT rats by leptin administration. In this analysis, livers were sampled for 6 h, a relatively short time after leptin administration to avoid the secondary effect of metabolic changes such as improvement of fatty liver. We did the same procedure in Lep(ob)/Lep(ob) mice and selected genes whose expression patterns were common in rat and mouse. We verified their gene expressions by real-time quantitative PCR. Finally, we identified eight genes that primarily respond to leptin in the liver commonly in rat and mouse. These genes might be important for the effect of leptin in the liver.

Leptin activates hepatic 5'-AMP-activated protein kinase through sympathetic nervous system and α1-adrenergic receptor: a potential mechanism for improvement of fatty liver in lipodystrophy by leptin.

BACKGROUND: AMPK activation promotes glucose and lipid metabolism. RESULTS: Hepatic AMPK activities were decreased in fatty liver from lipodystrophic mice, and leptin activated the hepatic AMPK via the α-adrenergic effect. CONCLUSION: Leptin improved the fatty liver possibly by activating hepatic AMPK through the central and sympathetic nervous systems. SIGNIFICANCE: Hepatic AMPK plays significant roles in the pathophysiology of lipodystrophy and metabolic action of leptin. Leptin is an adipocyte-derived hormone that regulates energy homeostasis. Leptin treatment strikingly ameliorates metabolic disorders of lipodystrophy, which exhibits ectopic fat accumulation and severe insulin-resistant diabetes due to a paucity of adipose tissue. Although leptin is shown to activate 5'-AMP-activated protein kinase (AMPK) in the skeletal muscle, the effect of leptin in the liver is still unclear. We investigated the effect of leptin on hepatic AMPK and its pathophysiological relevance in A-ZIP/F-1 mice, a model of generalized lipodystrophy. Here, we demonstrated that leptin activates hepatic AMPK through the central nervous system and α-adrenergic sympathetic nerves. AMPK activities were decreased in the fatty liver of A-ZIP/F-1 mice, and leptin administration increased AMPK activities in the liver as well as in skeletal muscle with significant reduction in triglyceride content. Activation of hepatic AMPK with A769662 also led to a decrease in hepatic triglyceride content and blood glucose levels in A-ZIP/F-1 mice. These results indicate that the down-regulation of hepatic AMPK activities plays a pathophysiological role in the metabolic disturbances of lipodystrophy, and the hepatic AMPK activation is involved in the therapeutic effects of leptin.

Functional magnetic resonance imaging analysis of food-related brain activity in patients with lipodystrophy undergoing leptin replacement therapy.

CONTEXT: Lipodystrophy is a disease characterized by a paucity of adipose tissue and low circulating concentrations of adipocyte-derived leptin. Leptin-replacement therapy improves eating and metabolic disorders in patients with lipodystrophy. OBJECTIVE: The aim of the study was to clarify the pathogenic mechanism of eating disorders in lipodystrophic patients and the action mechanism of leptin on appetite regulation. SUBJECTS AND INTERVENTIONS: We investigated food-related neural activity using functional magnetic resonance imaging in lipodystrophic patients with or without leptin replacement therapy and in healthy controls. We also measured the subjective feelings of appetite. RESULTS: Although there was little difference in the enhancement of neural activity by food stimuli between patients and controls under fasting, postprandial suppression of neural activity was insufficient in many regions of interest including amygdala, insula, nucleus accumbens, caudate, putamen, and globus pallidus in patients when compared with controls. Leptin treatment effectively suppressed postprandial neural activity in many of these regions of interest, whereas it showed little effect under fasting in patients. Consistent with these results, postprandial formation of satiety feeling was insufficient in patients when compared with controls, which was effectively reinforced by leptin treatment. CONCLUSIONS: This study demonstrated the insufficiency of postprandial suppression of food-related neural activity and formation of satiety feeling in lipodystrophic patients, which was effectively restored by leptin. The findings in this study emphasize the important pathological role of leptin in eating disorders in lipodystrophy and provide a clue to understanding the action mechanism of leptin in human, which may lead to development of novel strategies for prevention and treatment of obesity.

Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice.

Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic ß-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 µg·kg⁻¹·day⁻¹), amylin (A; 100 µg·kg⁻¹·day⁻¹), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPKα2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes.

An alpha-glucosidase inhibitor, voglibose, reduces oxidative stress markers and soluble intercellular adhesion molecule 1 in obese type 2 diabetic patients.

Postprandial hyperglycemia and hyperlipidemia are considered risk factors for cardiovascular disease. This study was designed to elucidate whether improving the postprandial state by voglibose, an alpha-glucosidase inhibitor, leads to the reduction of oxidative stress markers and soluble adhesion molecules in obese type 2 diabetic patients. A total of 30 Japanese obese type 2 diabetic patients were randomly assigned and treated for 3 weeks with either diet alone (the control group) or diet plus voglibose (0.9 mg daily) (the voglibose group) (n=15 each). Analysis of the diurnal metabolic profiles revealed a significant reduction of postprandial hyperglycemia and hyperlipidemia in the voglibose group relative to the control group (P<.05), despite the similar improvement in body mass index and hemoglobin A(1c) in both groups. Voglibose also decreased significantly the plasma levels of soluble intercellular adhesion molecule 1 and urinary excretion of 8-iso-prostaglandin F(2)alpha and 8-hydroxydeoxyguanosine (P<.01) and C-reactive protein (P<.05) relative to the control group. In conclusion, this study represents the first demonstration that voglibose reduces oxidative stress generation and soluble intercellular adhesion molecule 1 in parallel with the reduction of postprandial hyperglycemia and hyperlipidemia in obese type 2 diabetic patients.

Pathophysiogical role of leptin in lifestyle-related diseases. Studies with transgenic skinny mice overexpressing leptin.

Leptin is a major adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure. Plasma leptin concentrations are elevated in obese subjects, suggesting its pathophysiological role in obesity-related lifestyle-related diseases. We have recently succeeded in the generation of transgenic skinny mice overexpressing leptin. They exhibit increased glucose metabolism and insulin sensitivity accompanied by a significant increase in insulin signaling for glucose utilization in the skeletal muscle and liver. They also show blood pressure elevation through the sympathetic activation. Introduction of the lethal yellow agouti (A(y)) allele into transgenic skinny mice results in late-onset obesity and diabetes with blood pressure elevation similar to those found in nontransgenic agouti mice (A(y)/+ mice). After caloric restriction, blood pressure elevation is reversed but insulin resistance still remains in A(y)/+ mice in parallel with a reduction of plasma leptin concentrations. By contrast, blood pressure elevation is sustained but insulin resistance is reversed in transgenic mice overexpressing leptin with the A(y) allele (Tg/+:A(y)/+ mice), which remain hyperleptinemic. Collectively, our data suggest the pathophysiologic and therapeutic implication of leptin in obesity-related insulin resistance and hypertension.