A set of clinical trials examining youth and adults with type 2 diabetes or impaired glucose tolerance has found that disease progression in adults slowed during medical treatment but resumed after treatment stopped.
Youth on the same treatment had markedly poorer outcomes with continued disease progression both during and after the treatment.
This research, funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), was published June 9 in the journals Diabetes and Diabetes Care and presented at the American Diabetes Association Scientific Sessions in San Francisco. NIDDK is part of the National Institutes of Health.
The Restoring Insulin Secretion (RISE) Adult and Pediatric Medication Studies compared the use of different treatments among adults aged 20-65 and youth aged 10-19 with impaired glucose tolerance or early onset type 2 diabetes with the aim of preserving beta cell function – key to the body’s ability to make and release insulin.
In the adult study, participants were randomly assigned to receive either long-acting insulin (glargine) for three months followed by nine months of metformin, the drug liraglutide in combination with metformin for 12 months, metformin alone for 12 months, or a placebo.
Researchers wanted to see whether early aggressive treatment could have a lasting effect on slowing or stopping the decline of beta cell function that occurs in people with type 2 diabetes.
Participants were monitored for three additional months after treatments ended.
Results showed that adult participants had improvements in beta cell function and blood glucose control while on the treatments, with those in the liraglutide plus metformin group showing the most improvement after 12 months.
However, these improvements did not persist among any of the groups after treatment ended.
“The RISE medication studies show that these treatments for type 2 diabetes do not make lasting changes to beta cells,” said study chair Dr. Steven Kahn from the Veteran’s Affairs Puget Sound Health Care System and University of Washington School of Medicine.
“For adults, we saw that the treatment options were equally effective while people were actively on them – but people need to stay on treatment to maintain the benefits.”
In a companion paper, findings from the adult study were compared to those from the RISE Pediatric Medication Study published in 2018, which showed that beta cell function declined in the two youth treatment groups during active treatment, and worsened after treatment ended.
The RISE Adult and Pediatric Medication Studies were designed together to enable direct comparison of the effect of treatment on youth and adults.
The youth study compared the use of three months of insulin glargine followed by metformin for nine months to metformin alone for 12 months.
Insulin glargine and metformin are the only U.S. Food and Drug Administration-approved medications for youth with type 2 diabetes.
“Though the medications’ effectiveness for adults while on treatment is reassuring, the poor results for youth in the study, both during and after treatment, underscore the continued urgent need for new approaches to prevent and treat type 2 diabetes in youth, since the disease progresses more rapidly given the same treatment as adults,” said Dr. Ellen Leschek, a study author and the NIDDK project scientist for RISE.
This close comparison between adults and youth receiving the same type 2 diabetes treatments supports earlier research suggesting the disease is more aggressive in youth than adults, and points to new areas of research that may help explain why.
“The RISE studies show that type 2 diabetes affects youth differently, and more aggressively, than adults, said NIDDK Director Dr. Griffin P. Rodgers.
“These findings demonstrate the need for continued research to identify new treatment strategies to control and treat type 2 diabetes, and underscore the need to focus on prevention efforts, especially for youth.”
What is type 2 diabetes?
Diabetes mellitus is a term that covers a multitude of problems with many etiologies, unified by one common feature: the pathological elevation of blood glucose.
Sustained hyperglycemia leads to tissue damage in susceptible organs and eventually results in secondary complications including retinopathy, nephropathy, peripheral neuropathy, cardiovascular disease and stroke [1–3].
Diabetes currently affects 387 million people worldwide, and this number is predicted to increase to 592 million by 2035 .
The dramatic rise in the disease in recent years not only causes individual misery, but also places an enormous and increasing burden on healthcare systems and the global economy [5,6].
Indeed, many countries spend as much as 10 % of their healthcare budget on treating diabetes and its complications.
Type 2 diabetes (T2D) is the most common form of the disease, accounting for approximately 90 % of cases .
It has a strong genetic component that is amplified by factors such as age, obesity, diet, physical activity and pregnancy.
T2D is characterized by insufficient secretion of insulin from the β-cells of the pancreatic islets, coupled with impaired insulin action in target tissues such as muscle, liver and fat (a condition termed insulin resistance).
Hyperglycemia results when insulin secretion is unable to compensate for insulin resistance .
Insulin resistance is increased during obesity, which explains, at least in part, why T2D risk is enhanced by obesity.
The regulation of glucose homeostasis by insulin is summarized in Fig. 1.
Type 1 diabetes (T1D) is much less common than T2D, accounting for <10 % of cases.
It is precipitated by an autoimmune attack on the β-cells that results in an insulin deficient state, although a small number of functioning β-cells may remain .
Typically, T1D presents in childhood or young adulthood.
In addition, there are rare inherited monogenic forms of diabetes that usually present in early life, and account for only 1 to 2 % of all diabetes cases.
Unlike T2D, where it is believed multiple genes predispose to the disease, monogenic diabetes is caused by mutations in a single gene.
Many of these genes encode transcriptional regulators, metabolic enzymes and ion channels that regulate β-cell stimulus-secretion coupling, or they may affect the development of the pancreas.
Interestingly, common genetic variants in many of the genes known to cause monogenic diabetes enhance T2D risk; thus, their study may help elucidate the etiology of T2D.
T1D must be treated by insulin injections, due to the lack of β-cells.
Therapy for T2D consists initially of dietary control and lifestyle modifications, followed by oral hypoglycemic agents, which may increase insulin secretion (for example, sulfonylureas) or reduce insulin resistance or hepatic glucose output (for example, metformin).
If these fail to control hyperglycemia, then insulin is given. Monogenic diabetes is treated in different ways according to the gene involved.
Why are there no other hormones that can substitute for insulin?
Most control systems, including physiological ones, have built-in redundancy, which ensures that when one system fails another takes over.
For example, several hormones can elevate blood glucose. However, only insulin can reduce blood glucose.
At first this might seem surprising, but it is worth remembering that too much insulin has far more immediate and devastating effects than too little insulin.
If blood glucose falls below 2 mmol/l for as little as 5 minutes, it can cause lethal brain damage.
By contrast, it is only when blood glucose is chronically elevated over many weeks and months, due to a sustained lack of insulin, that the complications of diabetes are produced.
Thus, insulin is a ‘Goldilocks’ hormone in that both too much and too little are dangerous.
But although lack of insulin, and the consequent diabetes, receives much attention, an acute excess of insulin is far more damaging.
Insulin’s other function – its ability to enhance growth – is mirrored by several hormones, such as insulin-like growth factor 1 and 2. It is only the role of insulin in glucose homeostasis that is unique.
We therefore speculate that the danger of hypoglycemia is the reason for the unique ability of insulin, acting via a single receptor, to lower blood glucose.
In our evolutionary history, when humans battled with inadequate food and unplanned exercise (escaping predators) hypoglycemia was more likely than hyperglycemia.
In this situation, a single means of lowering blood glucose is advantageous as there is less chance of inadvertent hypoglycemia.
By contrast, the presence of numerous feedback systems to bolster blood sugar is beneficial.
Although T2D is an increasing problem in societies today, in evolutionary terms it is of little significance because it generally presents after an individual’s reproductive age.
Furthermore, it is only in very recent times that we have been exposed to the plentiful availability of high calorie diets and sedentary lifestyles that drive obesity and T2D.Go to:
How do β-cells avoid inappropriate insulin secretion?
β-cells have evolved important metabolic features to avoid excessive insulin secretion and hypoglycemia, particularly during exercise.
First, insulin secretion is exquisitely sensitive to changes in blood glucose.
This is achieved by coupling glucose metabolism with insulin secretion via changes in intracellular ATP levels, β-cell electrical activity and insulin vesicle release. When blood glucose rises, most of the glucose taken up by the β-cell is metabolized via oxidative phosphorylation, thereby elevating intracellular ATP.
This closes KATP channels, so triggering β-cell electrical activity and an influx of calcium (via voltage-gated calcium channels) that, in turn, stimulates insulin release (Fig. 2).
Conversely, when blood glucose levels fall, insulin secretion is rapidly switched off due to a reduction in intracellular ATP in β-cells, leading to opening of KATP channels, membrane hyperpolarization, reduced calcium entry and thereby inhibition of insulin secretion (Fig. 2).
Second, a number of metabolic genes that are widely expressed in other tissues are not expressed in pancreatic β-cells [9–11]. Such ‘disallowed’ genes include those encoding lactate dehydrogenase (LDHA) and the monocarboxylate transporter 1 (MCT1/SLC16A1), which are involved in the metabolism of lactate and pyruvate.
This prevents insulin secretion in response to circulating lactate and pyruvate during exercise.
Mutations in the SLC16A1 gene that result in its aberrant expression in β-cells provoke exercise-induced hypoglycemia by enabling pyruvate-induced insulin secretion [12,13]. In early humans, exercise-induced hypoglycemia could be lethal as it would impede escape from a predator; the absence of MCT1 ensures insulin secretion remains switched off during exercise.
Similarly, adrenaline inhibits insulin secretion, ensuring blood glucose levels do not drop during exercise or the ‘fight-or-flight’ response.
More information: undefined undefined. Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on β-Cell Function: Comparison of Responses In Youth And Adults, Diabetes(2019). DOI: 10.2337/db19-0299
undefined undefined. Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes, Diabetes Care (2019). DOI: 10.2337/dc19-0556
Journal information: Diabetes , Diabetes Care
Provided by National Institute of Diabetes and Digestive and Kidney Diseases