scholarly journals Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway

2015 ◽  
Vol 112 (8) ◽  
pp. 2503-2508 ◽  
Author(s):  
May-Yun Wang ◽  
Hai Yan ◽  
Zhiqing Shi ◽  
Matthew R. Evans ◽  
Xinxin Yu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Insulin Treatment ◽  
Glucagon Secretion ◽  
Glucagon Receptor ◽  
Acute Increase ◽  
Deficient Mice ◽  
Hba1c Levels

Insulin monotherapy can neither maintain normoglycemia in type 1 diabetes (T1D) nor prevent the long-term damage indicated by elevated glycation products in blood, such as glycated hemoglobin (HbA1c). Here we find that hyperglycemia, when unaccompanied by an acute increase in insulin, enhances itself by paradoxically stimulating hyperglucagonemia. Raising glucose from 5 to 25 mM without insulin enhanced glucagon secretion ∼two- to fivefold in InR1-G9 α cells and ∼18-fold in perfused pancreata from insulin-deficient rats with T1D. Mice with T1D receiving insulin treatment paradoxically exhibited threefold higher plasma glucagon during hyperglycemic surges than during normoglycemic intervals. Blockade of glucagon action with mAb Ac, a glucagon receptor (GCGR) antagonizing antibody, maintained glucose below 100 mg/dL and HbA1c levels below 4% in insulin-deficient mice with T1D. In rodents with T1D, hyperglycemia stimulates glucagon secretion, up-regulating phosphoenolpyruvate carboxykinase and enhancing hyperglycemia. GCGR antagonism in mice with T1D normalizes glucose and HbA1c, even without insulin.

scholarly journals Impacts of pre- and postnatal nutrition on glucagon regulation and hepatic signalling in sheep

2018 ◽  
Vol 238 (1) ◽  
pp. 1-12
Author(s):  
Bishnu Adhikari ◽  
Prabhat Khanal ◽  
Mette Olaf Nielsen
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Glucagon Secretion ◽  
Late Gestation ◽  
Plasma Glucagon ◽  
Glucagon Receptor ◽  
Protein Requirements ◽  
Daily Energy ◽  
Obesogenic Diet ◽  
Prenatal Undernutrition

To evaluate the long-term impacts of early-life nutritional manipulations on glucagon secretion and hepatic signalling, thirty-six twin-pregnant ewes during their last trimester were exposed to NORM (fulfilling 100% of daily energy/protein requirements), HIGH (fulfilling 150/110% of daily energy/protein requirements) or LOW (50% of NORM) diets. Twin lambs were assigned after birth to a moderate (CONV) or high-carbohydrate high-fat (HCHF) diet until 6 months. Then, responses in plasma glucagon concentrations and glucagon ratios relative to previously reported values for insulin, glucose and lactate were determined after intravenous bolus injections of glucose or propionate (fed and 2-day fasting state). Hepatic mRNA expressions of glucagon receptor (GCGR), glucose-6-phosphatase (G6PC), phosphoenolpyruvate carboxykinase (PEPCK) and fructose 1,6-biphosphatase (FBP) were also determined in a sub group of autopsied lambs. Expression of GCGR and all three enzymes were supressed by prenatal LOW compared to NORM (except PEPCK) and HIGH (except FBP) nutrition. The postnatal HCHF diet reduced plasma glucagon responses to propionate and hepatic mRNA expression of all genes. In response to propionate, insulin/glucagon ratio was decreased (fasted state), but lactate/glucagon and glucose/glucagon increased in HCHF compared to CONV lambs. In conclusion, prenatal undernutrition and postnatal overnutrition had similar long-term implications and reduced hepatic glucagon signalling. Glucagon secretory responses to propionate were, however, not related to the prenatal nutrition history, but negatively affected by the postnatal obesogenic diet. The pancreatic α-cell compared to β-cells may thus be less sensitive towards late gestation malnutrition, whereas hepatic glucagon signalling appears to be a target of prenatal programming.

scholarly journals Complete Long-Term Recovery of  -Cell Function in Autoimmune Type 1 Diabetes After Insulin Treatment

Diabetes Care ◽  
2004 ◽  
Vol 27 (5) ◽  
pp. 1207-1208 ◽  
Author(s):  
B. Karges ◽  
I. Durinovic-Bello ◽  
E. Heinze ◽  
B. O. Boehm ◽  
K.-M. Debatin ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Treatment ◽  
Cell Function

Intensive Treatment of Type-1 Diabetes The Balance of Benefits and Risks in the DCCT/EDIC Study

2006 ◽  
Vol 00 (02) ◽  
Author(s):  
Saul Genuth
Keyword(s):  
Clinical Trial ◽  
Type 1 Diabetes ◽  
Insulin Treatment ◽  
Intensive Treatment ◽  
Diabetic Coma ◽  
Follow Up Study ◽  
Trial Testing

With the discovery of insulin in 1921 and its rapid introduction into therapy in 1922, the complexion of type-1 diabetes changed completely. From a disease that inevitably led to death in diabetic coma within a few short years, type-1 diabetes morphed into a chronic disease as, in the 1930s, diabetic retinopathy, nephropathy, and neuropathy emerged as major complications. These complications afflicted sufferers with loss of vision, renal failure, pain, amputations, and death from cardiovascular disease (CVD) after 30–40 years. There ensued a long-standing debate as to whether these complications were caused by hyperglycemia and other consequences of insufficiently normalized metabolism or were simply an intrinsic parallel manifestation of diabetes that could not be prevented by insulin therapy. This question of whether normalization of blood glucose with intensive treatment would reduce the risk of diabetic complications compared with then-conventional insulin treatment, which only minimized or eliminated symptoms resulting from glycosuria, prevented spontaneous diabetic ketoacidosis and avoided hypoglycemia, could only be definitively answered by a long-term, randomized clinical trial testing the glucose hypothesis. Thus, the Diabetes Control and Complications Trial (DCCT) emerged, followed by the Epidemiology of Diabetes Interventions and Complications (EDIC) observational follow-up study of the same cohort of research volunteer patients.

scholarly journals AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes

2020 ◽  
Author(s):  
Angela Kim ◽  
Jakob G. Knudsen ◽  
Joseph C. Madara ◽  
Anna Benrick ◽  
Thomas Hill ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Alpha Cells ◽  
Glucagon Receptor ◽  
Major Barrier ◽  
Neuron Activation ◽  
Circulating Levels

AbstractHypoglycaemia is a major barrier to the treatment of diabetes. Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon – the body’s principle blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. In isolated islets, varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor that stimulates glucagon secretion in vivo remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor (V1bR). Activation of AVP neurons in vivo increased circulating AVP, stimulated glucagon release and evoked hyperglycaemia; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of dehydration and hypoglycaemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata, which are known to be activated by hypoglycaemia, drive AVP neuron activation in response to insulin-induced hypoglycaemia. Hypoglycaemia also increases circulating levels of copeptin (derived from the same pre-pro hormone as AVP) levels in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with type 1 diabetes, hypoglycaemia failed to increase both plasma copeptin and glucagon. These findings provide a new mechanism for the central regulation of glucagon secretion in both health and disease.

Evaluation of gastric emptying and neuropathy in short- and long-term type-1 diabetes

2006 ◽  
Vol 44 (05) ◽  
Author(s):  
T Várkonyi ◽  
É Börcsök ◽  
R Takács ◽  
R Róka ◽  
C Lengyel ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gastric Emptying ◽  
Short And Long Term ◽  
Term Type

Short and long-term glycemic variability associated with severe hypoglycemia and retinopathy in type 1 diabetes mellitus

2020 ◽  
Author(s):  
Martín Borja Sanz ◽  
Gimeno Sergio Roman ◽  
Peteiro Miranda Carlos Miguel ◽  
Ortez Toro Jose Jorge ◽  
Ana Agudo ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Severe Hypoglycemia ◽  
Glycemic Variability ◽  
Short And Long Term
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