Abnormal Alpha-Cell Function in Diabetes

Müller, W.; Faloona, Gerald R.; Aguilar-Parada, E; Unger, Roger H

doi:10.1056/nejm197007162830301

Cited by 563 publications

(92 citation statements)

References 10 publications

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“…Besides, the paradoxical rise of plasma glucagon was seen not only in rats given a diabetogenic dose of Sz, but also in those given the same dose of Sz with nicotinamide, and Sz with picolinamide, while the insulin response to glucose was not impaired in the pretreated animals. Oral glucose loading caused a decrease in plasma glucagon in normal human subjects (Muller et al, 1970) but not in normal control rats used in this study. The reasons for this are unclear.…”

Section: Discussioncontrasting

confidence: 51%

The effect of streptozotocin on the pancreatic a cell function.

et al. 1979

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SynopsisThe effect of a single i.v. injection of30, 50, and65mg of streptozotocin (Sz) per kg of body weight on blood glucose, plasma insulin and glucagon levels was studied in rats. Responses to glucose of these three parameters were also examined in rats one week after the administration of various doses of Sz alone, Sz with nicotinamide or with picolinamide.Nicotinamide, 500mg/kg, and picolinamide, 250 mg/kg, were given i.p. 15m in before the injection of 65mg/kg of Sz.The triphasic pattern was observed after the injection of 65mg/kg of Sz not only in blood glucose and plasma insulin but also in plasma glucagon level fluctuations, the last of which showed a similar pattern to that of blood glucose responses.Further, the initial hyperglucagonemia had a delay of2hr in onset, when treated with30 and50mg/kg of Sz, respectively. Oral glucose loading resulted in a significant increase of plasma glucagon levels in rats injected with 30 and 50mg/kg of Sz, respectively.The paradoxical rise of plasma glucagon and glucose intolerance was observed in rats given Sz with nicotinamide, and Sz with picolinamide, as well as in those given Sz alone, 65mg/kg, while there was no significant difference in insulin responses between the pretreated groups of rats and controls.These results suggest that streptozotocin, even in a nondiabetogenic dose, has effect(s) on the A cell function, and that nicotinamide and picolinamide are active in protecting B cells against the cytotoxic effect, but they do not modify the effect of Sz on the A cell function.

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Section: Discussioncontrasting

confidence: 51%

The effect of streptozotocin on the pancreatic a cell function.

et al. 1979

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“…This concept is important for understanding the key role of the islet beta cells for the development of IGT and type 2 diabetes: if beta cell compensation to insulin resistance fails, glucose homeostasis deranges, which will result in IGT and type 2 diabetes [3]. However, we, and others, have demonstrated that glucagon secretion is also important for the development of IGT and type 2 diabetes, in view of the hyperglucagonaemia and increased glucagon secretion which accompany these conditions [4][5][6][7][8][9][10][11][12]. This raises the issue of the relationship between insulin resistance and glucagon secretion under normal conditions.…”

Section: Discussionmentioning

confidence: 97%

“…Also, the augmented suppression by glucose would not be explained by such a mechanism. Interestingly, subjects with IGT and type 2 diabetes have reduced suppression by glucose of glucagon secretion [4][5][6][7][8][9][10][11][12]. It remains to be established whether failure of the augmenting action of glucose to suppress glucagon levels in insulin resistance represents the mechanism that initiates IGT.…”

Section: Discussionmentioning

confidence: 99%

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Glucagon secretion in relation to insulin sensitivity in healthy subjects

Åhrén

2005

Diabetologia

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Aims/hypothesis: The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions. Materials and methods: A total of 155 healthy women with NGT (aged 53-70 years) underwent a glucose-dependent arginine-stimulation test for evaluation of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8±0.1 mmol/l) and after raising blood glucose concentrations to 14.8±0.1 and 29.8±0.2 mmol/l. The acute glucagon response (AGR) to arginine during the three glucose levels (AGR 1 , AGR 2 , AGR 3 ) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic-hyperinsulinaemic clamp study for estimation of insulin sensitivity. Results: Insulin sensitivity was normally distributed, with a mean of 73.2±29.3 (SD) nmol glucose kg −1 min −1 /pmol insulin l −1 . When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity and AGR 2 was r=−0.38 (p<0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p<0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion. Conclusions/ interpretation: The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes during the development of insulin resistance.

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“…NAFLD patients both with and without type 2 diabetes display fasting hyperglucagonemia (Bernsmeier et al 2014, Junker et al 2016. In fact, the suppression of plasma glucagon in response to a meal or hyperglycemia is impaired or eliminated in prediabetic and diabetic individuals (Muller et al 1970, Unger et al 1972, Rohrer et al 2012, Foghsgaard et al 2016. Glucose-mediated inhibition of glucagon secretion from pancreatic alpha cells occurs indirectly and relies on paracrine signaling from insulin secreting beta cells (Le Marchand & Piston 2010).…”

Section: Introductionmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

156

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Abnormal Alpha-Cell Function in Diabetes

Cited by 563 publications

References 10 publications

The effect of streptozotocin on the pancreatic a cell function.

The effect of streptozotocin on the pancreatic a cell function.

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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