Pancreatic beta cell function (synonyms ''G_β'' or, if calculated from fasting concentrations of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

and

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

, HOMA-Beta or SPINA-GBeta) is one of the preconditions of euglycaemia, i.e. normal blood sugar regulation. It is defined as insulin secretory capacity, i.e. the maximum amount of insulin to be produced by

beta cell Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vi ...

s in a given unit of time.

Physiology and pathophysiology

Beta cells play a paramount role in

glucose homeostasis Blood sugar regulation is the process by which the levels of blood sugar, the common name for glucose dissolved in blood plasma, are maintained by the body within a narrow range. This tight regulation is referred to as glucose homeostasis. Insul ...

. Progressive loss of insulin secretory capacity is a key defect associated with the transition from a healthy glycaemic state to

hyperglycaemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluco ...

, characteristic of untreated

diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

. In type 1 diabetes mellitus and pancreatogenic diabetes

destruction is a primary event from the perspective of the

feedback loop Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause and effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handle ...

. In type 2 diabetes beta cell dysfunction is an essential constituent as well, but subsequent to the development of

insulin resistance Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...

. Other mechanisms, including lipotoxicity, amyloid deposition,

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

, mitochondrial dysfunction,

ER stress The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...

and

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

may be involved as well. The beta cell loss in type 2 diabetes is mainly caused by reduced beta cell number rather than size. Hyperglycaemia becomes clinically significant once insulin over-secretion can no longer compensate for the degree of insulin resistance. It remains an unsolved question if impaired pancreatic beta cell function or hypersecretion of insulin represent the primary event in the pathogenesis of type 2 diabetes. Both scenarios may be cause and consequence, and it has been postulated that the direction of causality depends on the respective subtype of diabetes. Therefore, they may be part of a complex feedback loop involving glucose toxicity leading to a biphasic response, thereby preventing neoplastic effects of dynamical compensation by mutant takeover.

Assessing beta cell function

Measuring beta-cell function is a challenge, since insulin secretory capacity cannot be readily assessed. Therefore, indirect methods of measurement have been developed. They include dynamic and static function tests.

Single-point measurements

One-time measurements of certain hormones or metabolites provide some limited information. Examples are: * Fasting glucose concentration * Fasting or random

C-peptide The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum levels ...

concentration Although single-point measurements have the benefit of being convenient and inexpensive, they are generally not regareded as sufficiently informative for early diagnosis of impaired glucose homeostasis or early-stage type 1 diabetes.

Dynamic function tests

Dynamic function tests for beta-cell function include: * Oral glucose tolerance testing (OGTT) * Intravenous glucose tolerance tests (IVGTT) * Meal tolerance tests * Hyperglycaemic clamp

Static function tests

Static function tests for the assessment of beta-cell function comprise: * Insulin-glucose ratio * Amended insulin-glucose ratio * HOMA-Beta *

SPINA-GBeta SPINA-GBeta is a calculated biomarker for pancreatic beta cell function. It represents the maximum amount of insulin that beta cells can produce per time-unit (e.g. in one second). The method of calculation is based on a time-discrete nonlinear f ...

Challenges and limits

Measuring beta-cell function requires the rate of secretion to be interpreted in relation to the prevailing glucose concentration. Therefore, a mathematical model is needed that links the time courses of insulin secretion and glucose concentration as a mechanistic causal relationship. Glucoregulatory hyperbola

Additionally, beta-cell function has to be interpreted in light of the prevailing insulin sensitivity. This is necessary since the beta cell mass is adjusted as required by dynamical compensation, giving rise to a hyperbolic relationship between insulin sensitivity and beta cell function. In the state of insulin resistance beta cells proliferate and their secretory capacity subsequently rises. One possibility to address this relation is to resort to a normalization of beta cell function based on a disposition metric. The

disposition index The Disposition index (DI) is a measure for the loop gain of the insulin-glucose feedback control system. It is defined as the product of insulin sensitivity times the amount of insulin secreted in response to blood glucose levels. "Metabolicall ...

, calculated as product of insulin sensitivity and beta cell function, is assumed to be a constant during the development of insulin resistance. It is generally assumed that the glucose tolerance of an individual is related to the disposition index. In this model, different values of glucose tolerance are represented by different hyperbolas, so that within one hyperbola the product of insulin sensitivity and beta cell function remains a constant. In summary, to provide a meaningful mechanistic explanation of insulin-glucose homeostasis, beta cell function and insulin sensitivity have to be assessed simultaneously and it is necessary to interpret all observations in the context of insulin sensitivity or resistance.

References

{{Disease of the pancreas and glucose metabolism Diabetes Human cells Endocrine pancreas Peptide hormone secreting cells