The main goal in the treatment of diabetes is to maintain the blood glucose level within a physi- ological range, e.g., by decreasing insulin resis- tance, by activating endogenous insulin secretion, or by exogenous administration of recombinant insulin.
Of note, increasing endogenous insulin secre- tion requires yet functional β cells.
In T1DM, where the functional β-cell mass is already signifi cantly reduced once symp- toms occur, patients immediately require insulin replacement therapy.
Traditionally, exogenous insulin is adminis- tered by subcutaneous injection. Today, insulin therapy is individualized and varies regarding insulin preparation (rapid- and short-acting insulin vs. intermediate- and long-acting insulin), applica- tion system (pen vs. insulin pump), and regimen (conventional vs. intensifi ed regimen; see below).
To mimic physiological insulin secretion, an intensifi ed regimen is recommended for T1DM that combines the application of a long-acting insulin (e.g., insulin glargine or insulin detemir), mimicking basal insulin secretion, with premeal bolus application of a rapid- or short-acting insu- lin (e.g., insulin lispro or insulin aspart) adjusted for the amount of carbohydrate intake and current blood glucose level.
By contrast, current treatment guidelines in T2DM recommend a stepwise approach starting with lifestyle changes, such as physical activity and weight reduction, and follow up with drug treatment, typically with metformin (see below and Fig. 2 ). Initially, most patients can be treated with an oral glucose-lowering drug (see below and Fig. 2 ). However, over time, due to the pro- gressive nature of the disease, many patients require a combination of two or more antidia- betic drugs (Fig. 2 ). The benefi t of glucose-low- ering treatment is judged by the concentration of glycosylated hemoglobin (called HbA1c)
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representing a patient’s average blood glucose level over the past 4 months. A level of 7 % is often recommended.
To date, there are several glucose-lowering, oral drugs on the market that differ in their modes of action and safety profi les (Fig. 2 ). These include oral drugs that directly stimulate insulin secretion (sulfonylureas, meglitinides), reduce hepatic glucose output and increase insulin sensitivity (biguanides such as metformin), delay the digestion and absorption of intestinal car-
bohydrates (α-glucosidase inhibitors), improve insulin action (thiazolidinediones such as piogli- tazone), or increase endogenous concentrations of the incretin glucagon-like-peptide-1 (GLP-1, see chapter “ Overview ” under the part “Pancreas”) by inhibiting the protease dipeptidyl peptidase-4 (DPP-4), which degrades GLP-1 (DPP-4 inhibi- tors). In addition, homologues or mutated forms of GLP-1 (GLP-1 receptor agonists) can be injected, increasing insulin secretion in response to food intake and promoting β-cell survival.
1st step 2nd step 1st tier2nd tier
3rd step
Lifestyle intervention (weight loss, physical activity, diet)
+ Metformin
If metformin is contraindicated:
- α-Glucosidase inhibitor - Meglitinide
- Sulphonylurea -Thiazolidinedione (- Insulin) Hepatic glucose output
Insulin resistance
Disease progression
(HbA1c >7 % after 3 months of treatment)
+ Basal insulin (especially if HbA1c >8.5 %)
+ Sulphonylureas
Hyperglycemia
Insulin secretion Combined therapy
Metformin + thiazolidinedione Metformin + GLP-1 receptor agonist
Metformin + sulphonylurea + thiazolidinedione Other therapy: a-glucosidase inhibitor, DPP-4 inhibitor
Disease progression
(HbA1c > 7% after 3 months of treatment) Metformin + intensified insulin therapy
Fig. 2 Long-term management of hyperglycemia in type 2 diabetes mellitus. Treatment of type 2 diabetes mellitus (T2DM) generally starts with lifestyle intervention and an oral antidiabetic drug, typically metformin (1st step). If glycated hemoglobin (HbA1c) continues to be >7 % after 3 months of therapy, treatment is intensifi ed by addition of a second oral antidiabetic drug, typically a sulfonylurea, or basal insulin therapy (2nd step, 1st tier). Importantly, treatment of T2DM is individualized for each patient.
Depending on comorbidities and/or contraindications to
certain drugs, some patients might require medications other than metformin or sulfonylureas to achieve glyce- mic control (2nd step, 2nd tier). If the disease further pro- gresses (as indicated by HbA1c measurement after 3 months of therapy), a combination of metformin and an intensifi ed insulin therapy is recommended (3rd step) (Adapted from the American Diabetes Association/
European Association for the Study of Diabetes (ADA/
EASD) consensus algorithm [ 26 ]) Diabetes Mellitus
168
However, many approved antidiabetic drugs can cause serious adverse effects, such as hypo- glycemia (insulin, sulfonylureas, meglitinides), weight gain (insulin, sulfonylureas, meglitinides, thiazolidinediones), gastrointestinal disturbances (α-glucosidase inhibitors, biguanides), peripheral edema, fractures, and an increased risk for con- gestive heart failure (see chapter “ Heart failure ”) without an associated increase in mortality (pio- glitazone), or severe lactic acidosis (biguanides) [ 21 , 22 ]. Incretin homologues have been shown to induce pancreatitis and possibly pancreatic hyperplasia [ 23 ].
Perspectives
Recently, SGLT-2 inhibitors have been developed to inhibit renal glucose reabsorption, thus lead- ing to increased glucose excretion and reduction of hyperglycemia [ 24 ]. Moreover, novel insulin delivery systems are currently tested such as sen- sor-augmented insulin pumps or fully automated closed-loop systems (also referred to as the “arti- fi cial pancreas”) that continuously sense the blood glucose level and automatically deliver insulin [ 25 ].
Importantly, none of the current therapies is curative, necessitating lifelong diabetes treat- ment. Thus, identifi cation of a curative drug taken for a short period of time to prevent β-cell destruction and trigger β-cell regeneration is the long-term goal of current diabetes research. A more detailed understanding of the molecular mechanisms leading to progressive β-cell death and dysfunction in diabetes is therefore required to develop such treatments.
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