Abnormal Alpha Cell Function in Diabetics Response to Insulin

Unger, Roger H; Madison, Leonard L.; Müller, W.

doi:10.2337/diab.21.5.301

Cited by 88 publications

(47 citation statements)

References 3 publications

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“…It has been shown that the administration of anti-insulin serum to perfused rat pancreas markedly increased glucagon secretion and abolished the ability of an increase in the glucose concentration to decrease glucagon secretion (27,33,34). Acute insulin deficiency in humans (35,36), as well as alloxan-or streptozotocininduced diabetes in animals, are associated with hyperglucagonemia (37). It is therefore likely that the decrease in intra-islet insulin contributed in some way to the increased glucagon secretion that we observed in response to mild hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Insulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog

et al. 2002

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In the present study, we examined how the arterial insulin level alters the ␣-cell response to a fall in plasma glucose in the conscious overnight fasted dog. Each study consisted of an equilibration (؊140 to ؊40 min), a control (؊40 to 0 min), and a test period (0 to 180 min), during which BAY R 3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally to decrease glucose output in each of four groups (n ‫؍‬ 5). In group 1, saline was infused. In group 2, insulin was infused peripherally (3.6 pmol ⅐ kg ؊1 ⅐ min ؊1 ), and the arterial plasma glucose level was clamped to the level seen in group 1. In group 3, saline was infused, and euglycemia was maintained. In group 4, insulin (3.6 pmol ⅐ kg ؊1 ⅐ min ؊1 ) was given, and euglycemia was maintained by glucose infusion. In group 1, drug administration decreased the arterial plasma glucose level (mmol/l) from 5.8 ؎ 0.2 (basal) to 5.2 ؎ 0.3 and 4.4 ؎ 0.3 by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels (pmol/l) and the hepatic portalarterial difference in plasma insulin (pmol/l) decreased (P < 0.01) from 78 ؎ 18 and 90 ؎ 24 to 24 ؎ 6 and 12 ؎ 6 over the first 30 min of the test period. The arterial glucagon levels (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) rose from 43 ؎ 5 and 5 ؎ 2 to 51 ؎ 5 and 10 ؎ 5 by 30 min (P < 0.05) and to 79 ؎ 16 and 31 ؎ 15 (P < 0.05) by 90 min, respectively. In group 2, in response to insulin infusion, arterial insulin (pmol/l) was elevated from 48 ؎ 6 to 132 ؎ 6 to an average of 156 ؎ 6. The hepatic portal-arterial difference in plasma insulin was eliminated, indicating a complete inhibition of endogenous insulin release. The arterial glucagon level (ng/l) and the hepatic portalarterial difference in plasma glucagon (ng/l) did not rise significantly (40 ؎ 5 and 7 ؎ 4 at basal, 44 ؎ 4 and 9 ؎ 4 at 90 min, and 44 ؎ 8 and 15 ؎ 7 at 180 min). In group 3, when euglycemia was maintained, the insulin and glucagon levels and the hepatic portal-arterial difference remained constant. In group 4, the arterial plasma glucose level remained basal (5.9 ؎ 1.1 mmol/l) throughout, whereas insulin infusion increased the arterial insulin level to an average of 138 ؎ 6 pmol/l. The hepatic portal-arterial difference in plasma insulin was again eliminated. Arterial glucagon level (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) did not change significantly (43 ؎ 2 and 9 ؎ 2 at basal, 39 ؎ 3 and 9 ؎ 2 at 90 min, and 37 ؎ 3 and 7 ؎ 2 at 180 min). Thus, a difference of ϳ120 pmol/l in arterial insulin completely abolished the response of the ␣-cell to mild hypoglycemia. Diabetes 51:3033-3042, 2002

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Section: Discussionmentioning

confidence: 99%

Insulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog

et al. 2002

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“…In these experiments, pan-'Assay of glucagon became available after normals (nos. [1][2][3][4][5] and diabetics (nos. 1-12) had already been studied.…”

Section: Methods Animalsmentioning

confidence: 99%

“…However, impaired insulin secretion may not be the only factor responsible for the abnormal glucose metabolism. Fasting hyperglucagonemia (2,3), lack of suppression of plasma glucagon by glucose (4,5), and excessive glucagon responses to amino acids (2, 6, 7) have been reported to occur in diabetics. These observations suggest that abnormal pancreatic alpha-cell function may also be involved.…”

Section: Introductionmentioning

confidence: 99%

Abnormal Secretion of Insulin and Glucagon by the In Vitro Perfused Pancreas of the Genetically Diabetic Chinese Hamster

Frankel¹,

Gerich²,

Hagura³

et al. 1974

J. Clin. Invest.

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Therefore, to characterize pancreatic islet function, dynamic insulin and glucagon release from normal and nonketotic diabetic hamster pancreases in response to glucose (300 mg/100 ml) and theophylline (10 mM), infused singly and together, was studied in vitro.20-min glucose infusions of normal hamster pancreases caused biphasic insulin release, consisting of a rapid first peak and a gradually rising second phase, similar to that reported for man in vivo. Both phases were significantly reduced in the diabetic pancreases. Theophylline alone stimulated similar nonphasic insulin release in both the normal and the diabetic pancreases. Glucose and theophylline together caused greater insulin release than either stimulant alone in both normals and diabetics; however, the diabetic response was still subnormal.Glucose suppressed glucagon release from normal pancreases; suppression was significantly impaired in diabetics. Theophylline stimulated nonphasic glucagon release in both the normals and diabetics. Glucose partially suppressed the theophylline-stimulated release in both groups.Insulin/glucagon molar ratios of the diabetics were consistently subnormal, although individual hormone levels often overlapped into the normal range.This work was presented in part at the Western Section of the American Federation for Clinical Research, Carmel, Calif., 2 February 1973 (Clin. Res. 21: 273)

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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

153

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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 Diabetics Response to Insulin

Cited by 88 publications

References 3 publications

Insulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog

Insulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog

Abnormal Secretion of Insulin and Glucagon by the In Vitro Perfused Pancreas of the Genetically Diabetic Chinese Hamster

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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