Congenital Glucagon-like Peptide-1 Deficiency in the Pathogenesis of Protracted Diarrhea in Mitchell-Riley Syndrome.

CONTEXT: Mitchell-Riley syndrome due to RFX6 gene mutations is characterized by neonatal diabetes and protracted diarrhea. The RFX6 gene encodes a transcription factor involved in enteroendocrine cell differentiation required for beta-cell maturation. In contrast to the pathway by which RFX6 mutations leads to diabetes, the mechanisms underlying protracted diarrhea are unknown. OBJECTIVE: To assess whether glucagon-like peptide-1 (GLP-1) was involved in the pathogenesis of Mitchell-Riley syndrome protracted diarrhea. METHODS: Two case report descriptions. in a tertiary pediatric hospital. "Off-label" treatment with liraglutide. We describe 2 children diagnosed with Mitchell-Riley syndrome, presenting neonatal diabetes and protracted diarrhea. Both patients had nearly undetectable GLP-1 plasma levels and absence of GLP-1 immunostaining in distal intestine and rectum. The main outcome was to evaluate whether GLP-1 analogue therapy could improve Mitchell-Riley syndrome protracted diarrhea. RESULTS: "Off-label" liraglutide treatment, licensed for type 2 diabetes treatment in children, was started as rescue therapy for protracted intractable diarrhea resulting in rapid improvement during the course of 12 months. CONCLUSION: Congenital GLP-1 deficiency was identified in patients with Mitchell-Riley syndrome. The favorable response to liraglutide further supports GLP-1 involvement in the pathogenesis of protracted diarrhea and its potential therapeutic use.

Deficiency of glucagon gene-derived peptides induces peripheral polyneuropathy in mice.

Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg-/-) mice were examined. The gcg-/- mice showed tactile allodynia and thermal hyperalgesia at 12-18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg-/- mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.

Endogenous glucagon-like peptide- 1 and 2 are essential for regeneration after acute intestinal injury in mice.

OBJECTIVE: Mucositis is a side effect of chemotherapy seen in the digestive tract, with symptoms including pain, diarrhoea, inflammation and ulcerations. Our aim was to investigate whether endogenous glucagon-like peptide -1 and -2 (GLP-1 and GLP-2) are implicated in intestinal healing after chemotherapy-induced mucositis. DESIGN: We used a transgenic mouse model Tg(GCG.DTR)(Tg) expressing the human diphtheria toxin receptor in the proglucagon-producing cells. Injections with diphtheria toxin ablated the GLP-1 and GLP-2 producing L-cells in Tg mice with no effect in wild-type (WT) mice. Mice were injected with 5-fluorouracil or saline and received vehicle, exendin-4, teduglutide (gly2-GLP-2), or exendin-4/teduglutide in combination. The endpoints were body weight change, small intestinal weight, morphology, histological scoring of mucositis and myeloperoxidase levels. RESULTS: Ablation of L-cells led to impaired GLP-2 secretion; increased loss of body weight; lower small intestinal weight; lower crypt depth, villus height and mucosal area; and increased the mucositis severity score in mice given 5-fluorouracil. WT mice showed compensatory hyperproliferation as a sign of regeneration in the recovery phase. Co-treatment with exendin-4 and teduglutide rescued the body weight of the Tg mice and led to a hyperproliferation in the small intestine, whereas single treatment was less effective. CONCLUSION: The ablation of L-cells leads to severe mucositis and insufficient intestinal healing, shown by severe body weight loss and lack of compensatory hyperproliferation in the recovery phase. Co-treatment with exendin-4 and teduglutide could prevent this. Because both peptides were needed, we can conclude that both GLP-1 and GLP-2 are essential for intestinal healing in mice.

Investigating Factors Involved in Post Laparoscopic Sleeve Gastrectomy (LSG) Neuropathy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has gained popularity as the leading bariatric procedure for the treatment of morbid obesity. Due to the rising numbers of bariatric surgeries, neurologic complications have become increasingly recognized. Our aim was to examine biochemical and hormonal factors that are associated with neuropathy post-LSG. METHODS: Thirty-two patients were included: 16 patients with neuropathy in the neuropathic group (NG) and 16 patients without neuropathy in the control group (CG). Diagnosis was made by a consultant neurologist, and blood samples were taken to examine vitamin deficiencies and hormones involved in neuropathy. RESULTS: There was no significant difference between the BMI (p = 0.1) in both groups as well as excess weight loss percentages post-LSG at 12 months (p = 0.6). B12 levels were within normal range, but higher in NG (p = 0.005). Vitamin B1 and B2 levels were significantly lower in NG; p values are 0.000 and 0.031, respectively. Vitamin B6 levels were significantly higher in NG (p = 0.02) and copper levels were lower in NG (p = 0.009). There was no significant difference in GLP-1 response in both groups. CONCLUSION: Our data showed post-LSG neuropathy is associated with lower levels of vitamin B1, B2, and copper, plus patients who are older in age. Vitamin B6 was significantly higher in the NG, which is, at toxic levels, associated with neuropathy. No difference in preoperative BMI, excess weight loss percent at 1 year, and GLP-1 levels was found. Larger data is required to validate our results.

Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength.

UNLABELLED: A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION: The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS: Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS: As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS: This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

Type 2 diabetes and the evolving paradigm in glucose regulation.

Type 2 diabetes mellitus (T2DM) is a multisystem disease comprising numerous metabolic defects that contribute to the development of hyperglycemia. Although insulin resistance in the skeletal muscle and liver together with progressive beta cell failure are traditionally thought of as the core defects responsible for the development and progression of hyperglycemia, research over the past 2 decades has revealed a far more complex interaction of organs and tissues, with consequences for the fundamental understanding of the mechanisms of glucose disequilibrium and the nature of T2DM itself. Dysfunctions in the gastrointestinal tract, adipose tissue, pancreatic alpha cells, brain, and kidneys have all been described, and together with insights into the involvement of liver, muscle, and beta cells produce a more robust picture of T2DM. The function of the kidneys in abnormal glucose homeostasis is a striking example of this evolution in T2DM knowledge, as the role of glucose transporters in regulating plasma glucose levels and producing hyperglycemia has enhanced current understanding of T2DM. As pathophysiologic mechanisms and defects continue to be discovered, they offer an expansion of potential targets for treatment of T2DM.